Substituted-acyclic terpene compound

ABSTRACT

Acyclic terpene compounds useful as intermediates or producing sarcophytol A which have an anti-carcinogenic promotor activity and anti-tumor activity, which compounds are shown by the general formula (I):    &lt;IMAGE&gt;  (I)  [wherein R is a group of formula:   &lt;IMAGE&gt;   or   &lt;IMAGE&gt;

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of Ser. No. 07/962,016, filed Oct. 15,1992, now allowed, which is a continuation of Ser. No. 07/786,071, filedOct. 31, 1991, now abandoned, which is a continuation-in-part of Ser.No. 07/730,811, filed on Jul. 25, 1991, now abandoned, which is thenational phase application of International Application No.PCT/JP90/01555, filed on Nov. 29, 1990.

FIELD OF THE ART

The present invention relates to novel substituted-acyclic terpenecompounds. More particularly, the present invention is directed tosubstituted-acyclic terpene compounds useful as intermediates forproducing sarcophytol A which have an anti-carcinogenic promotoractivity and anti-tumor activity.

BACKGROUND OF THE INVENTION

The sarcophytol A was reported to exhibit anti-carcinogenic promotoractivity [Cancer Surveys, 2, 540 (1983); Taisha, Vol. 25, SpecialEdition, Gan '88,3 (1988)] and anti-tumor activity [Japanese PatentPublication 20213/1988], whereby it has been regarded as a usefulanti-tumor agent. As can be seen from the following structure,sarcophytol A is a cembrane type diterpene-alcohol containing oneconjugated double bond and two other double bonds in the 14-memberedring. ##STR2##

The present inventors studied with the aim of developing a syntheticmethod of sarcophytol A and proposed a synthetic route shown by thefollowing synthetic route 1 [JP Patent Appln. 181710/1989; filing date:Jul. 14, 1991]. ##STR3## wherein R⁷ is C₁ -C₄ lower alkyl group orphenyl group; X¹ is a halogen atom or a leaving group such as OSO₂ R⁹and the like; R⁸ is a hydrogen atom, or trimethylsilyl group or1-ethoxyethyl group; and R⁹ is lower alkyl group such as methyl group orethyl group, substituted alkyl group such as trifluoromethyl group,phenyl group or substituted phenyl group such as toluyl group, mesitylgroup or the like.

Although the previously proposed method according to the above syntheticroute 1 gives the objective sarcophytol A, it has some problems asfollows:

1) it requires as the starting material a valuable compound (A), namely"E,E'-farnesol" of a structure essential for the production ofsarcophytol A;

2) the oxidation of the terminal methyl group of compound (B) withselenium dioxide is poor in both the selectivity and yield.

3) the process to prepare the Compound (F) by reducing compound (D) toCompound (E), and oxidizing the latter is complicated and inefficient.

Thus, the process shown by the synthetic route 1, especially thatconcerned with the production of the intermediate (F) from the startingcompound (A) is not optimal for the industrial production of sarcophytolA, and a more efficient method for preparing the compound (F) has beendemanded.

Under these circumstances, the present inventors have continuouslyinvestigated earnestly with the aim of developing a more efficient andsimple method for producing the intermediate (F), thereby providing aprocess applicable to the industrial production of sarcophytol A, andhave now found that certain novel substituted-acyclic terpene compoundsare useful for the establishment of the purpose of the invention.

DISCLOSURE OF THE INVENTION

The present invention provides acyclic terpene compounds of the generalformula (I): ##STR4## [wherein R is a group of formula: ##STR5##(wherein R¹ is cyano group or formyl group; R² is a hydrogen atom or--CO₂ R³ ; R³ is C₁ -C₄ alkyl group; R⁴ is --C.tbd.CH or --CH═CH₂); X isa hydrogen atom, a halogen atom, or a group of formula: --OR⁵ or --OSO₂R⁶ (wherein R⁵ is a hydrogen atom 1-alkoxyalkyl group, tetrahydrofurylgroup, an tetrahydropyranyl group, silyl group substituted with C₁ -C₅alkyl group or phenyl group; R⁶ is C₁ -C₄ alkyl group optionallysubstituted with halogen atom, or phenyl group optionally substitutedwith C₁ -C₄ alkyl group); and n is an integer of 0 to 2 with the provisothat when R is a group of formula: ##STR6## X must be --OR⁵ and n mustbe 0; when R¹ is formyl group, X is not a halogen atom or --OSO₂ R⁶ ;when R⁵ is a hydrogen atom, R² is not a hydrogen atom; and when R⁵ is1-ethoxyethyl group, R³ is not a methyl group].

The terms used for the definition of the compound (I) are explainedbelow.

In the definition of R³, examples of "C₁ to C₄ lower alkyl group "include a straight or branched alkyl group containing 1 to 4 carbonatoms, for example, methyl group, ethyl group, n-propyl group, isopropylgroup, butyl group, isobutyl group, sec-butyl group, tert-butyl groupand the like.

In the definition of R⁵, the term "C₁ to C₅ lower alkyl group" refers tothe above "C₁ to C₄ lower alkyl group" and pentyl group, isopentylgroup, neopentyl group and 1,2-dimethylbutyl group. Examples of"1-alkoxyalkyl group" include methoxymethyl group, 1-ethoxyethyl groupand the like. Examples of "silyl group substituted with C₁ -C₅ alkylgroup or phenyl group" include trimethylsilyl group,t-butyldimethylsilyl group, t-butyldiphenylsilyl group and the like.Examples of "acyl group" include acetyl group, propionyl group, benzoylgroup and the like.

In the definition of R⁶, the term "halogen atom" includes fluorine,chlorine, bromine and the like. Examples of "C₁ -C₄ alkyl groupoptionally substituted with halogen atom" include methyl group, ethylgroup, propyl group, trifluoromethyl group, trichloromethyl group andthe like. Examples of "phenyl group optionally substituted with C₁ -C₄alkyl group" include phenyl group, p-tolyl group and the like.

PREFERRED EMBODIMENT OF THE INVENTION

Typical compounds represented by the general formula (I) are shownbelow. However, these are given only for illustrative purpose and neverto restrict the scope of the invention.

    ______________________________________                                        Compound No.    X                                                             ______________________________________                                        (1) Compound (I) wherein R is                                                  ##STR7##                                                                     1) R.sup.1 = CN, n = 0                                                         ##STR8##                                                                      1              H                                                              2              OH                                                             3              Cl                                                             4              OSO.sub.2 CH.sub.3                                             5                                                                                             ##STR9##                                                      6              OSi(CH.sub.3).sub.3                                            7                                                                                             ##STR10##                                                     8              OCHCH.sub.3 (O)C.sub.2 H.sub.5                                2) R.sup.1 = CN, n = 1                                                         ##STR11##                                                                     9              H                                                             10              OH                                                            11              Cl                                                            12              Br                                                            13              OSO.sub.2 CH.sub.3                                            14                                                                                             ##STR12##                                                    15              OCHCH.sub.3 (OEt)                                             16              OCH.sub.2 OCH.sub.3                                           17                                                                                             ##STR13##                                                    3) R.sup.1 = CN, n = 2                                                         ##STR14##                                                                    18              H                                                             19              OH                                                            20              Cl                                                            21              OSO.sub.2 CH.sub.3                                            22              OCOCH.sub.3                                                   4) R.sup.1 = CHO, n = 0                                                        ##STR15##                                                                    23              H                                                             24              OH                                                            25              OSi(CH.sub.3).sub.2.C.sub.4 H.sub.9 .sup.t                    26              OCHCH.sub.3 (OC.sub.2 H.sub.5)                                27                                                                                             ##STR16##                                                    5) R.sup.1 = CHO, n = 1                                                        ##STR17##                                                                    28              H                                                             29              OH                                                            30              OCHCH.sub.3 (OC.sub.2 H.sub.5)                                31              OCH.sub.2 OCH.sub.3                                           32                                                                                             ##STR18##                                                    33              OCOCH.sub.3                                                   34                                                                                             ##STR19##                                                    6) R.sup.1 = CHO, n = 2                                                        ##STR20##                                                                    35              H                                                             36              OH                                                            37              OCHCH.sub.3 (OC.sub.2 H.sub.5)                                38              OCOCH.sub.3                                                   (2) Compound (I) wherein R is                                                  ##STR21##                                                                     ##STR22##                                                                    Compound                                                                      NO.         R.sup.2      R.sup.5                                              ______________________________________                                         1          CO.sub.2 CH.sub.3                                                                          CH.sub.2 OCH.sub.3                                    2          CO.sub.2 CH.sub.3                                                                           ##STR23##                                            3          CO.sub.2 CH.sub.3                                                                          Si(CH.sub.3).sub.2 C.sub.4 H.sub.9 .sup.t              4         CO.sub.2 C.sub.2 H.sub.5                                                                   Si(CH.sub.3).sub.2 C.sub.4 H.sub.9 .sup.t             5          CO.sub.2 CH.sub.3                                                                          H                                                     6          CO.sub.2 CH.sub.3                                                                          COCH.sub.3                                            7          CO.sub.2 CH.sub.3                                                                           ##STR24##                                            8          H                                                                                           ##STR25##                                            9          H            CH.sub.2 OCH.sub.3                                   10          H                                                                                           ##STR26##                                           11          H            Si(CH.sub.3).sub.2 C.sub.4 H.sub.9 .sup.t            12          H            COCH.sub.3                                           14          H                                                                                           ##STR27##                                           (3) Compound (I) wherein R is                                                  ##STR28##                                                                     ##STR29##                                                                    15          CHCH.sub.2                                                                                  ##STR30##                                           16          CHCH.sub.2                                                                                  ##STR31##                                           17          CHCH.sub.2   CH.sub.2 OCH.sub.3                                   18          CHCH.sub.2   Si(CH.sub.3).sub.2 C.sub.4 H.sub.4 .sup.t            19          CHCH.sub.2   H                                                    20          CHCH.sub.2   COCH.sub.3                                           21          CHCH.sub.2                                                                                  ##STR32##                                           22          CCH                                                                                         ##STR33##                                           23          CCH                                                                                         ##STR34##                                           24          CCH          CH.sub.2 OCH.sub.3                                   25          CCH          Si(CH.sub.3).sub.2 C.sub.4 H.sub.9 .sup.t            26          CCH          H                                                    27          CCH          COCH.sub.3                                           28          C CH                                                                                        ##STR35##                                           ______________________________________                                    

Although all the compounds of the formula (I) including thoseillustrated in the above are useful as intermediates for the productionof sarcophytol A, there are certain preferable compounds, that is, forexample, those wherein n is 0 or 1. Especially preferred compounds canbe found among the illustrated ones as follows:

(1) compound Nos. 1, 2, 3, 9, 10, 11, 12, 13, 14, 15, 17, 23, 24, 28,29, 30, 32 and 33; and

(2) compounds Nos. 2, 6, 8, 10, 12, 15, 16, 19, 20, 22 and 23.

Preparation of the compound (I) of the present invention is describedbelow according to the type of the directed compound.

(1) Compound of general formula (I) wherein R is a group of formula:##STR36## 1) Compounds wherein R¹ is CN and X is H

Among the compounds of this type, those wherein n is 0, 1 or 2 can beprepared from corresponding starting materials, that is, those wherein nis 0 are from geranial, those wherein n is 1 are from farnesol, andthose wherein n is 2 are from geranyl geranial, by reacting eachstarting material with 1 to 20 mol equivalent of Wittig-Horner reagentin the presence of less than 1 mol equivalent of a base (for theWittig-Horner reagent) in an appropriate solvent.

The Wittig-Horner reagent which can be used is, for example,2-(dimethylphosphono)isovaleronitrile,2-(diethylphosphono)isovaleronitrile, or the like. Generally 1 to 10 molequivalent of such a reagent is used for the starting material.

Examples of appropriate solvents include ether solvents such astetrahydrofuran (THF), diethyl ether and the like, hydrocarbon solventssuch as benzene, toluene, n-hexane and the like and aprotic polarsolvents such as dimethylformamide (DMF) and the like. Preferredsolvents are hydrocarbon solvents such as toluene, n-hexane and thelike.

Examples of bases include metal hydrides such as sodium hydride,potassium hydride and the like, organic metals such s n-butyllithium,lithium diisopropylamide, lithium-bis-(trimethylsilyl)amide, potassiumbis-(trimethylsilyl)amide and the like, metal alkoxides such as sodiummethoxide, potassium t-butoxide and the like. Generally, less than 1 molequivalent of such a base is used for the Wittig-Horner reagent. In thisreaction, it is possible to control the steric isomerism at the doublebond of the product by selecting the solvent and the base.

The reaction is usually carried out at temperature from -100° to 100°C., preferably from -80° to 50° C., more preferably -70° to 0° C.

Each starting compound, when reacted with an anion which is generatedduring the reaction between the compound and a selected base in thepresence of a selected Wittig-Horner reagent at temperature within thecited range in a selected solvent, gives the corresponding product.Under these conditions, the reaction is usually complete in the periodfrom 30 minutes to 12 hours.

2) Compound (I) wherein R¹ is CHO and X is H

Compounds of this type can be prepared, for example, by reacting acompound prepared in above 1) with 1 to 10 mol equivalent of a metalhydride such as diisobutylaluminium hydride at temperature from -100° to150° C. in a hydrocarbon solvent such as toluene, n-hexane, heptane,benzene or the like, which is followed by hydrolysis.

3) Compounds (I) wherein X is OH

Compounds of this type can be prepared, for example, by reacting acompound prepared in above 1) or 2) with an equivalent amount to 50 molequivalent of t-butylhydroperoxide in the presence of 0.01 to 0.1 molequivalent of selenium dioxide at temperature from -20° to 50° C. over aperiod of 1 to 100 hours in a solvent such as methylenechloride or thelike.

4) Compounds (I) wherein R¹ is CN and X is a halogen atom

Compounds of this type can be prepared, for example, from an alcoholwherein R¹ is CN, obtained in above 3), by halogenating said allylicalcohol without allyl rearrangement. Such a reaction can be carried outby reacting the alcohol with 1.0 to 10 mol equivalent of carbontetrahalide in the presence of 1.0 to 10 mol equivalent of triphenylphosphine at temperature from room temperature to 100° C. over a periodof 1 to 8 hours in an inert solvent such as acetonitrile or the like. Incase of chlorination, carbon tetrachloride can be used as a solvent.Alternatively, it can be carried out by reacting 1.0 to 10 molequivalent of methanesulfonyl chloride together with a metal halide andγ-collidine at temperature from -40° C. to room temperature over aperiod of 1 to 10 hours.

5) Compounds wherein R¹ is CN and X is OSO₂ R⁶ (R⁶ is as defined above)

Compounds of this type can be prepared, for example, by reacting analcohol wherein R¹ is CN obtained in above 3) with 1.0 to 10 molequivalent of sulfonyl chloride such as methanesulfonyl chloride,p-toluenesulfonyl-chloride or sulfonyl anhydride such astrifluoromethanesulfonic anhydride in the presence of 1.0 to 10 molequivalent of amine such as triethylamine, pyridine or the like attemperature from -40° C. to room temperature over a period of 1 to 10hours in an ether solvent such as ethyl ether, tetrahydrofuran or thelike or a halogen solvent such as methylenechloride, chloroform or thelike, or pyridine in case it is used as a base.

6) Compounds wherein X is OR⁵ (R⁵ is as defined above)

a) Compounds wherein R⁵ is substituted silyl group

Compounds of this type can be prepared by reacting a compound obtainedin above 3) with 0.5 to 10 mol equivalent of a substituted silylchloride such as trimethylchlorosilane, t-butyldimethylchlorosilane orthe like in the presence of 0.5 to 10 mol equivalent of a base such astriethylamine, pyridine, imidazole or the like at temperature from -50°to 50° C. in an ether solvent such as ethyl ether, THF or the like, anaprotic polar solvent such as dimethylformamide or the like, a halogensolvent such as dichloromethane, chloroform or the like.

b) Compounds wherein R⁵ is 1-alkoxyalkyl group

Compounds of this type can be prepared by reacting a compound obtainedin above 3) with 0.5 to 10 mol equivalent of 1-haloalkyl ether such aschloromethylmethyl ether or chloromethyl-(2-methoxyethyl) ether or thelike together with 0.5 to 10 mol equivalent of a base such as sodiumhydride, potassium hydride, diisopropylamine, triethylamine or the likeat temperature from -50° to 50° in a solvent such as THF, DMF or thelike or without solvent; or with 1 to 10 mol equivalent of1-alkenylalkyl ether such as vinylethyl ether, dihydropyrane or the likein the presence of a catalytic amount to equivalent amount of mineralacid such as hydrochloric acid, sulfuric acid or the like, an organicacid such as p-toluenesulfonic acid, camphorsulfonic acid or the like ora salt such as pyridinium slat of p-toluenesulfonic acid or the like attemperature from -20° to 100° C. in an ether solvent such as diethylether, THF or the like, an ester solvent such as ethyl acetate or thelike, or a halogen solvent such as dichloromethane, chloroform or thelike.

c) Compounds wherein R⁵ is acyl group

Compounds of this type can be prepared by reacting a compound obtainedin above 3) with 1 to 10 mol equivalent of acyl halide such as acetylchloride, benzoyl chloride or the like or acid anhydride such as aceticanhydride, trichloroacetic anhydride or the like in the presence of 1 to10 mol equivalent of a base such as triethylamine, pyridine or the likeat temperature from -20 to 100° C. in a halogen solvent such asdichloromethane, chloroform or the like or an ether solvent such asethyl ether, THF or the like or a hydrocarbon solvent such as benzene,toluene, n-hexane or the like, or without solvent where a base serves asa solvent.

(2) Compound of general formula (I) wherein R is a group of formula:##STR37##

1) Compounds (I) wherein R⁵ is 1-alkoxyalkyl group, tetrahydrofuranylgroup or tetrahydropyranyl group, silyl group substituted with C₁ -C₅alkyl group or phenyl group and R₂ is CO₂ R³ (wherein R³ is as definedabove)

Compounds of this type can be prepared by substituting the hydroxylgroup at the 8 position of 8-hydroxygeranyl acetate with --OR⁵ (R⁵ is asdefined above) according to either of the following methods.

a) 8-Hydroxygeranyl acetate is reacted with 0.1 to 10 mol equivalent of1-haloalkyl ether such as chloromethylmethyl ether,chloromethyl-2-methoxyethyl ether or the like in the presence of 0.5 to10 mol equivalent of a base, for example, a metal hydride such as sodiumhydride, potassium hydride or the like, amines such as diisopropylamine,triethylamine or the like, or pyridine or the like at temperature rom-20° to +100° over a period of 5 minutes to 24 hours in a halogensolvent such as methylene chloride, chloroform or the like, an ethersolvent such as diethyl ether, tetrahydrofuran or the like, or ethylacetate or dimethylformamide or the like, or without solvent.

b) 8-Hydroxygeranyl acetate is reacted with 0.1 to 10 mol equivalent orvinyl ether such as ethylvinyl ether, dihydropyrane or the like in thepresence of a catalytic amount to equivalent amount of mineral acid suchas hydrochloric acid, sulfuric acid or the like, an organic acid such asp-toluenesulfonic acid, camphorsulfonic acid or the like, or a salt of astrong acid such as pyridinium salt of p-toluenesulfonic acid or thelike at temperature from -20° to +100° C. in a halogen solvent such asdichloromethane, chloroform or the like, an ether solvent such asdiethyl ether, tetrahydrofuran or the like, or ethyl acetate ordimethylformamide of the like, or without solvent.

c) 8-Hydroxygeranyl acetate is reacted with 0.1 to 10 mol equivalent oftrialkylsilyl halide such as trimethylsilyl chloride,t-butyldimethylsilyl chloride or the like in the presence of 0.1 to 10mol equivalent of a base such as nitrogen-containing compound such astriethylamine, dimethylaminopyridine, imidazole or the like, or metalhydride such as sodium hydride, potassium hydride or the like attemperature from -20° to +100° C. over a period of 5 minutes to 24 hoursin a halogen solvent such as methylene chloride, chloroform or the like,a hydrocarbon solvent such as hexane, benzene or the like, an ethersolvent such as diethyl ether, tetrahydrofuran or the like or ethylacetate, dimethylformamide, dimethyl sulfoxide or the like.

The resultant compound, when reacted, for example, with an alkali metalsalt of acetoacetic ester, gives the desired compound. Thus, thecompound is reacted with an alkali metal salt of an acetoacetic ester attemperature from -70° to +100° C. over a period of 30 minutes to 48hours in an aprotic polar solvent such as diethyl ether,tetrahydrofuran, dimethylformamide, dimethyl sulfoxide or the like togive the directed compound, where the alkali metal salt of anacetoacetic ester can be prepared by reacting an acetoacetic ester suchas ethyl acetoacetate, ethyl acetoacetate or the like with a metalhydride such as sodium hydride or the like, or a strong base such asn-butyllithium, lithium diisopropylamine or the like in the presence ofa palladium (0) chelate such as tetrakis(triphenylphosphine) palladiumand the like as a catalyst at temperature from -70° to +100° C. in anaprotic polar solvent such as diethyl ether, tetrahydrofuran,dimethylformamide, dimethyl sulfoxide or the like.

2) Compounds (I) wherein R⁵ is H and R² is CO₂ R³ (R³ is as definedabove)

Compounds of this type can be prepared by reacting a compound obtainedin above 1) with 0.1 to 10 mol equivalent of a mineral acid such ashydrochloric acid, sulfuric acid or the like, an organic strong acidsuch as p-toluenesulfonic acid or the like or a salt of a strong acidsuch as pyridinium salt of p-toluenesulfonic acid or the like in analcohol solvent such as methanol, ethanol or a the like or water, or amixed solvent thereof. Alternatively, it can be prepared by reacting thecompound obtained in 1) with 0.1 to 10 mol equivalent oftetraalkylammonium fluoride such as tetrabutylammonium fluoride orhydrogen fluoride in a protonic polar solvent such as methanol, ethanol,water or the like, an ether solvent as diethyl ether, tetrahydrofuran orthe like, or a mixed solvent thereof.

3) Compounds (I) wherein R⁵ is acyl group and R² is CO₂ R³ (R³ is asdefined above)

Compounds of this type can be prepared by reacting a compound obtainedin above 2) with 0.1 to 10 mol equivalent of acyl halide such as acetylchloride, benzoyl chloride or the like or acid anhydride such as aceticanhydride or the like in the presence of 0.1 to 10 mol equivalent of abase such as triethylamine, pyridine or the like at temperature from-20° to +100° C. in a halogen solvent such as dichloromethane or thelike, an ether solvent such as diethyl ether or the like, a hydrocarbonsolvent such as benzene, n-hexane or the like, or without solvent wherea base serves as a solvent.

4) Compounds (I) wherein R⁵ is a hydrogen atom, 1-alkoxyalkyl group,tetrahydrofuranyl group, tetrahydropyranyl group, silyl groupsubstituted with C₁ -C₅ alkyl group or phenyl group or acyl group and R²is a hydrogen atom.

Compounds of this type can be prepared through the decarboxylation ordecarboalkoxylation of a compound obtained in above 1), 2) or 3). Thedecarboxylation can be carried out by reacting said compound with 0.1 to10 mol equivalent of a metal hydroxide such as sodium hydroxide,potassium hydroxide or the like, metal alkoxide such as sodium methoxideor the like at temperature from 0° to 100° C. over a period of 10minutes to 24 hours for the hydrolysis or ester-exchanging reaction, andheating at temperature from 100° to 250° C. over a period of 30 minutesto 10 hours. The decarboalkoxylation which is carried out by reacting acompound with 0.1 to 10 mol equivalent of a metal halide such as sodiumchloride, sodium iodide or the like at temperature from 50° to 250° C.in an aprotic polar solvent such as dimethylformamide, dimethylsulfoxideor the like. (3) Compounds (I) wherein R is a group of formula:##STR38##

1) Compounds (I) wherein R⁵ is a hydrogen atom, 1-alkoxyalkyl,tetrahydrofuranyl or tetrahydropyranyl group, or silyl group substitutedwith C₁ -C₅ alkyl group or phenyl group and R⁴ is --CH═CH₂

Compounds of this type can be prepared by subjecting a compound obtainedin (2), 4) to an addition reaction, which is conducted by reacting saidcompound with 0.1 to 10 mol equivalent of a vinyl anion such as vinyllithium, vinyl magnesium bromide or the like at temperature from -50° to100° C. over a period of 30 minutes to 48 hours in an ether solvent suchas diethyl ether, tetrahydrofuran or the like or a hydrocarbon solventsuch as n-hexane, benzene or the like.

2) Compounds (I) wherein R⁵ is a hydrogen atom, 1-alkoxyalkyl group,tetrahydrofuranyl group, tetrahydropyranyl group or silyl groupsubstituted with C₁ -C₅ alkyl group or phenyl and R⁴ is --C.tbd.CH

Compounds of this type can be prepared by subjecting a compound obtainedin above (2), 4) to an addition reaction which is conducted by reactingsaid compound with 0.1 to 10 mol equivalent of a metal acetylide such aslithium acetylide, ethynyl magnesium bromide or the like at temperaturefrom +50° to +100° C. over a period of 30 minutes to 48 hours in anether solvent such as diethyl ether, tetrahydrofuran or the like or ahydrocarbon solvent such as n-hexane, benzene or the like.

3) Compounds (I) wherein R⁵ is acyl group and R⁴ is a group of --CH═CH₂or --C.tbd.CH

Compounds of this type can be prepared by reacting a compound obtainedin above (3), 1) or 2)(, in which R⁵ is a hydrogen atom and R⁴ is--CH═CH₂ --C.tbd.CH, with 0.1 to 10 mol equivalent of acyl halide suchas acetyl chloride, benzoyl chloride or the like or acid anhydride suchas acetic anhydride or the like in the presence of 0.1 to 10 molequivalent of a base such as triethylamine, pyridine or the like attemperature from -20° to +100° C. in a halogen solvent such asdichloromethane or the like, an ether solvent such as diethyl ether orthe like, a hydrocarbon solvent such as benzene, n-hexane or the like,or without solvent where a base serves as a solvent.

The above are examples of preferred procedures for the production of thecompounds of formula (I) of the invention. As one of skill in the artwill appreciate, the present invention is not restricted to thecompounds (I) produced by the above methods, but includes any compoundsof formula (I) prepared by other methods known to the art.

As mentioned above, the present invention makes it possible to obtainCompound (F), the key intermediate in the synthetic route 1 for theproduction of sarcophytol A, from a monoterpenoid which is cheap andeasy to obtain, by an improved and efficient process with avoiding theoxidation of alcohol to aldehyde of the previously provided method,reducing the total steps, and in high yield.

Thus, the present invention provides an industrially advantageoussynthetic route for preparing sarcophytol A.

Typical procedures for the production of the intermediate (F) in thesynthetic route 1 from various compounds (I) of the invention as thestarting material, and that for the production of the final product,sarcophytol A, will hereinafter be described.

(1) When the starting material is a compound (I) wherein X is a halogenatom, n is 1 and R is a group of formula: ##STR39##

Compound (F) in the above synthetic route 1 can be prepared by reactinga compound (I) as defined above with 0.1 to 10 mol equivalent ofdiisobutylaluminium hydride in a solvent such as toluene, benzene,n-hexane or the like at temperature from -100° to 100° C. andhydrolyzing the product.

(2) When the starting material is Compound (I') which is shown by theformula (I) wherein R⁵ is 1-alkoxyalkyl group and R is a group offormula: ##STR40## or Compound (I") which is shown by the formula (I)wherein R² is 1-alkoxyalkyl group and R is a group of formula: ##STR41##(wherein R⁵ and X are as defined above).

a) When the starting material is Compound (I')

Compound (A') can be prepared by subjecting the Compound (I') torearrangement reaction in the presence of 0.01 to 1 mol equivalent ofsilylvanadate such as tris(triphenylsilyl)vanadate,poly{(diphenylsilyl)vanadate} or the like at temperature from 100° to300° C. over a period of 30 minutes to 24 hours in a hydrocarbon solventsuch as undecane, xylene or the like, an ether solvent such asbis[2-(2-methoxyethoxy)-ethyl] ether or a mineral oil.

b) When the starting material is Compound (I")

An unsaturated aldehyde (A') can be prepared by reacting the Compound(I") with chromic oxides such as pyridinium chlorochromate or the likeat temperature from 0° to 100° C. over a period of 30 minutes to 24hours in a halogen solvent such as methylene chloride, chloroform or thelike, a hydrocarbon solvent such as n-hexane, benzene or the like, ordimethylformamide or the like.

c) Compound (B') can be prepared by reacting Compound (A') with 0.1 to10 mol equivalent of Wittig-Horner reagent such as2-(dimthylphosphono)isovaleronitrile,2-(diethylphosphono)isovaleronitrile or the like in an ether solventsuch as tetrahydrofuran, diethyl ether or the like, a hydrocarbonsolvent such as toluene, n-hexane or the like or an aprotic polarsolvent such as dimethylformamide, dimethyl sulfoxide or the like attemperature from -100° to +100° C., in the presence of less than 1 molequivalent (for the Wittig-Horner reagent) of a base, for example, metalhydride such as sodium hydride, potassium hydride or the like, organicmetal (e.g. n-butyllithium, lithium diisopropylamide) or metal alkoxidesuch as sodium methoxide potassium t-butoxide or the like while allowingcompound (A') to react with a generated anion.

Aldehyde (C') is prepared by reacting Compound (B') with 0.1 to 10 molequivalent of a metal hydride complex with as lithium aluminum hydrideor the like at temperature from -70° to +100° C. in an ether solventsuch as diethyl ether, tetrahydrofuran or the like or reacting with 0.1to 10 mol equivalent of a metal hydride such as diisobutylaluminiumhydride or the like at temperature from -70° to +100° C. over a periodof 5 minutes to 5 hours in a hydrocarbon solvent such as n-hexane,benzene or the like.

Aldehyde (C') is converted into alcohol (E') when treated with 0.1 to 10mol equivalent of a mineral acid such as hydrochloric acid, sulfuricacid or the like, an organic strong acid such as p-toluenesulfonic acidor a salt of a strong acid such as a pyridinium salt ofp-toluenesulfonic acid or the like in a solvent such as aqueousmethanol, aqueous ethanol, aqueous tetrahydrofuran, or a mixed solventthereof.

Compound (F) can be prepared from Compound (E') by halogenating theallylic alcoholic without allyl rearrangement. For example, Compound(E') is reacted with 0.1 to 10 mol equivalent of carbon tetrahalide inthe presence of 1.0 to 10 mol equivalent of triphenylphosphine in asolvent such as acetonitrile, dichloromethane or the like, in case ofchlorination, with carbon tetrachloride without solvent, at temperaturefrom -10° to +100° C. over a period of 10 minutes to 12 hours.Alternatively, Compound (E') is reacted with 0.1 to 10 mol equivalent ofsulfonyl halide such as methanesulfonyl chloride, p-toluenesulfonylchloride or the like together with a metal halide such as lithiumchloride in the presence of an amine such as pyridine, γ-collidine,lutidine or the like at temperature from -40° to +30° C. over a periodof 1 to 12 hours.

The final product, sarcophytol A, can be prepared be treating Compound(F) according to the procedure shown by the synthetic route 1 as shownbelow.

Process of the Synthetic Route 1

a) Preparation of Compound (G)

Thus, Compound (G) wherein R⁸ is trimethylsilyl group is prepared, forexample, by treating Compound (F) with 1.0 to 10 mol equivalent oftrimethylsilylnitrile in the presence of a catalytic amount of metalcyanide 18-crown-6-ether complex, an ammonium salt such astetraalkylammonium cyanide or the like at temperature from -20° to 50°C. over a period of 30 minutes to 5 hours in a solvent such as methylenechloride, chloroform, ethyl acetate or the like, or without solvent. Theresultant product can be converted into cyanohydrin wherein R⁸ ishydrogen by treating with 0.1-3N aqueous mineral acid such ashydrochloric acid, sulfuric acid or the like at 0° C. to roomtemperature over a period of 5 minutes to 5 hours or by treating with acatalytic amount to 10 mol equivalent of tetraalkylammonium salt such astetrabutylammonium fluoride or the like at temperature from -20° C. toroom temperature in a solvent such as tetrahydrofuran, dioxane or thelike.

Compound (G) wherein R⁸ is 1-ethoxyethyl group can be prepared byreacting the above cyanohydrin with 1.0 to 10 mol equivalent of ethylvinyl ether in the presence of a catalytic amount of mineral acid suchas hydrochloric acid, sulfuric acid or the like, an organic strong acidsuch as p-toluenesulfonic acid or the like, or a salt of strong acidsuch as p-toluenesulfonic acid or the like pyridinium salt attemperature from -20° C. to room temperature over a period of 30minutesto 5 hours in a solvent such as ethyl ether, ethyl acetate or the like.

b) Preparation of Compound (H)

Compound (H) wherein R⁸ is trimethylsilyl or 1-ethoxyethyl group can beprepared by reacting Compound (G) wherein R⁸ is trimethylsilyl group or1-ethoxyethyl group with 1.0 to 10 mol equivalent of a base such aslithium diisopropylamide, lithium bis-(trimethylsilyl) amide, sodiumhydride or the like at temperature from -70° to 100° C. over a period of5 minutes to 10 hours in an ether solvent such as ethyl ether,tetrahydrofuran or the like, an aromatic hydrocarbon solvent such asbenzene, toluene or the like or a saturated hydrocarbon solvent such asn-hexane, n-heptane or the like.

Compound (H) wherein R⁸ is a hydrogen atom is prepared by treating thecompound obtained above with 0.1-3N aqueous mineral acid such ashydrochloric acid, sulfuric acid or the like at temperature from 0° C.to room temperature over a period of 5 minutes to 5 hours in a solventsuch as tetrahydrofuran, methanol or the like or by treating with acatalytic amount to 10 mol equivalent of tetraalkylammonium salt such astetrabutylammonium fluoride at temperature from -20° C. to roomtemperature in a solvent such as tetrahydrofuran, dioxane or the like.

c) Preparation of a ketone, Compound (J)

The ketone (J) can be prepared by treating a solution of Compound (H)wherein R⁸ is a hydrogen atom in an organic solvent such as ethyl ether,ethyl acetate or the like with aqueous sodium bicarbonate at temperaturefrom 0° C. to room temperature over a period of 5 minutes to 5 hours, orby treating Compound H wherein R⁸ is trimethylsilyl group with acatalytic amount to 10 mole equivalent of an alkylammonium fluoride suchas tetrabutylammonium fluoride in a solvent such as aqueoustetrahydrofuran, dioxane or the like.

d) Preparation of sarcophytol A

Sarcophytol A can be prepared by reacting the ketone (J) thus obtainedwith 1.0 to 10 mol equivalent of a metal hydride such asdiisobutylaluminum hydride or the like or a metal complex such aslithium aluminum hydride or the like at temperature from -70° to 50° C.over a period of 5 minutes to 5 hours in an ether solvent such as ethylether, tetrahydrofuran or the like, an aromatic hydrocarbon solvent suchas benzene, toluene or the like or a saturated hydrocarbon solvent suchas n-hexane, n-heptane or the like.

Further, sarcophytol A in native form shown below is prepared bysubjecting ketone Compound (J) to asymmetric reduction with anasymmetrically-modified metal hydride or metal hydride complex.##STR42##

Examples of asymmetrically-modifying reagents used for preparingasymmetrically-modified metal hydride or metal hydride complex, whichare used in the asymmetric reduction, include asymmetric amino alcoholsprepared by converting carboxy group of optically-active amino acid suchas L- or D-proline, valine or the like into substituted alcohol group orsubstituted amino group [Bull. Soc. Chim. Belg. 97: 691 (1988); J. Chem.Soc. Perkin I 1673: (1983)]; asymmetric diamines [Bull. Chem. Soc. Japan51: 1869 (1978); Tetrahedron 37: 4111 (1981)], asymmetric alkaloids suchas L- or D-methylephedrine and the like [Chem. Pharm. Bull. 31: 837(1983)]; and (S)- or (R)-1,1'-bis-2-naphtol and the like.

Examples of metal hydrides or metal hydride complexes includediisobutylaluminium hydride, lithium aluminium hydride, sodiumborohydride and the like. An asymmetric reducing reagent can be preparedby reacting a metal hydride or metal hydride complex with 0.1 to 5 molequivalent, preferably 0.5 to 1.5 mol equivalent of the above-mentionedasymmetrically-modifying reagent, optionally in the presence of anadditive such as alkyl-substituted aniline, substituted aminopyridine,stannous chloride or the like at temperature from -50° to 50° C.,preferably from -20° C. to room temperature over a period of 10 minutesto 5 hours in an appropriate solvent to obtain a coordinated complex ofsaid asymmetrically-modifying reagent and metal hydride or metal hydridecomplex. Examples of appropriate solvents include ether solvents such asdiethyl ether, tetrahydrofuran and the like and hydrocarbon solventssuch as benzene, toluene, n-hexane and the like. A halogen solvent suchas dichloromethane and chloroform is also available in case metalhydride is used. Illustrative combinations are listed in the Table 1below.

                  TABLE 1                                                         ______________________________________                                        metal                                                                         hydride or                                                                    metal   asymmetric                                                            hydride modifying                                                             complex reagent            additive                                           ______________________________________                                        LiAlH.sub.4                                                                            ##STR43##                                                                                        ##STR44##                                         LiAlH.sub.4                                                                            ##STR45##         --                                                 LiAlH.sub.4                                                                            ##STR46##         --                                                 HAl(i-Bu).sub.2  (DIBAL)                                                               ##STR47##         SnCl.sub.2                                         BH.sub.3                                                                               ##STR48##         --                                                 BH.sub.3                                                                               ##STR49##         --                                                 ______________________________________                                    

Although the amount of the asymmetric reducing reagent to be reactedwith the macrocyclic ketone shown by the structure (J) is not critical,it is preferable to use 1 to 2 mol equivalent of asymmetric reducingreagent for the ketone considering the recovery of un-reacted startingmaterials and yield of the product. The reaction is usually conducted attemperature from -150° to 100° C., preferably from -100° C. to roomtemperature over a period of 10 minutes to 5 hours in the same solventas that used for the preparation of the asymmetric reducing reagent. Noregularity can be found between the absolute configuration of theproduct sarcophytol A (its native form is expressed by I_(R) andnon-native form I_(S) as shown below) and that of the asymmetricreducing reagent, which is attributable to the original compound in L-or D-form. The absolute configuration of the product varies depending onthe combination of the asymmetric reducing reagent and metal hydride ormetal hydride complex.

The by-product of the present method, sarcophytol A in non-native formof formula: ##STR50## when subjected to the conventional epimerizationreaction for hydroxyl group, easily gives the optically-activesarcophytol A (I_(S)) in native form after the inversion.

(3) When the starting material is a compound of formula (I) wherein n is1 and R is a group of formula: ##STR51## wherein R¹ is as defined above.##STR52## R⁹ : substituted sulfonyl group such as methanesulfonyl groupor p-toluenesulfonyl group.

Compound (K) in the above synthetic route 3 can be prepared by, forexample, reacting a compound of formula (I) wherein n is 1, X is ahydrogen atom and R is a group: ##STR53## with either of 1.0 to 10 molequivalent of metal hydride such as dibutylaluminium hydride or thelike, or a metal complex such as lithium aluminium hydride or the likeat temperature from -70° to 50° C. over a period of 5 minutes to 5 hoursin a ether solvent such as ethyl ether, tetrahydrofuran or the like, anaromatic hydrocarbon solvent such as benzene, toluene or the like or asaturated hydrocarbon solvent such as n-hexane, n-heptane or the like;or with 0.5 to 10 mol equivalent of metal hydride complex such as sodiumborohydride or the like at temperature -70° to 100° C. in a solvent suchas methanol, ethanol or the like.

The resulting Compound (K) is converted into Compound (L) through theepoxidation which is conducted by halogenating the Compound K with 0.1to 1 mol equivalent of a halogenating agent such as N-bromosuccinimide,N-chlorosuccinimide or the like at temperature from -20° to 100° C. overa period of 30 minutes to 5 hours in an aqueous solvent of awater-miscible solvent such tetrahydrofuran, dimethoxyethane or thelike, followed by treating with an aqueous solution of a base such assodium hydroxide, potassium hydroxide, sodium carbonate or the like, orafter the halogenation, isolating halohydrin, and treating it with abase such as sodium carbonate, sodium methoxide or the like in a solventsuch as methanol or tetrahydrofuran or the like; or by treating with 0.1to 1 mol equivalent of organic peracid such as m-chloroperbenzoic acid,peracetic acid or the like at temperature from -50° to 50° C. over aperiod of 30 minutes to 10 hours.

Compound (M) can be prepared by reacting Compound (L) with 0.1 to 10 molequivalent of metal alkoxide such as aluminium triisopropoxide or thelike at temperature from 50° to 200° C. in a solvent such as toluene,xylene or the like; or with 0.1 to 10 mol equivalent of a metal amidesuch as lithium diisopropylamide, lithium diethylamide or the like attemperature from -70° to 100° C. in a solvent such as diethyl ether,tetrahydrofuran or the like.

Compound (N) can be prepared by the sulfonylesterification of thediallyl alcohol (M). For example, Compound (M) is reacted with 0.1 to1.5 mol equivalent of a substituted sulfonyl chloride such asmethanesulfonyl chloride, p-toluenesulfonyl chloride or the like in thepresence of 0.1 to 10 mol equivalent of a base such as triethylamine,pyridine or the like at temperature from -70° to 100° C. in a halogensolvent such as dichloromethane, chloroform or the like or a ethersolvent such as diethyl ether, tetrahydrofuran or the like.

Compound (O) can be prepared, for example, by treating Compound (N) with0.1 to 10 mol equivalent of metal hydride such as sodium hydride,potassium hydride or the like or organic metal such as n-butyllithium,ethyl magnesium chloride or the like at temperature from -50° to 150° C.in an ether solvent such as diethyl ether, tetrahydrofuran or the like,a hydrocarbon solvent such as benzene, toluene, n-hexane or the like oran aprotonic polar solvent such as dimethylformamide, dimethyl sulfoxideor the like.

The resultant Compound (O) can be converted into sarcophytol A byreacting said Compound (O) with 0.1 to 10 mol equivalent of organicmetal such as n-butyl lithium, sec-butyl lithium, lithium diisopropylamide or the like at temperature from -100° to 100° C. in an ethersolvent such as diethyl ether, tetrahydrofuran or the like, ahydrocarbon solvent such as benzene, toluene, n-hexane or the like, orfurther adding hexamethylphosphoric triamide or the like to the solvent.

(4) When the starting material is a compound of formula I wherein n is 0and R is a group of formula: ##STR54## wherein R¹ is as defined above.##STR55##

Compound (A") in the above synthetic route 4 can be prepared from acompound (I) wherein R¹ is --CN, n is 0 and X is a hydrogen atom asmentioned above through epoxidation as follows. Thus, Compound (A") isprepared by halogenating a compound (I) with 0.1 to 1 mol equivalent ofa halogenating agent such as N-bromosuccinimide, N-chlorosuccinimide orthe like at temperature from -50° to 50° C. over a period of 30 minutesto 5 hours in an aqueous solvent of a water-misicible solvent suchtetrahydrofuran, dimethoxyethane or the like, followed by treating withan aqueous solution of a base such as sodium hydroxide, potassiumhydroxide, sodium carbonate or the like, or after the halogenation,separating halohydrine, and reducing it with a base such as sodiumcarbonate, sodium methoxide or the like in a solvent such as methanol orterahydrofuran or the like; or by treating the compound with 0.1 to 1mol equivalent of organic peracid such as m-chloroperbenzoic acid,peracetic acid or the like at temperature from - 50° to 50° C. over aperiod of 30 minutes to 10 hours.

Compound (B") is prepared by treating the above epoxy compound (A") with0.1 to 10 mol equivalent of metal alkoxide such as aluminiumtriisopropoxide or the like at temperature from 50° to 200° C. in asolvent such as toluene, xylene or the like; or with 0.1 to 10 molequivalent of a metal amide such as lithium diisopropylamide, lithiumdiethylamide or the like at temperature from -70° to 100° C. in asolvent such as diethyl ether, tetrahydrofuran or the like.

The aldehyde compound (C") can be prepared by, for example, through theClaisen rearrangement, which is conducted by reacting Compound (B") with1.0 to 100 mol equivalent of alkyl vinyl ether such as ethyl vinyl etheror the like in the presence of 0.1 to 5 mol equivalent of a mercury saltsuch as mercury acetate or the like at temperature from 0° to 100° C. togive the vinyl ether of Compound (B") or leading said Compound (B") to3-alkoxyacrylic acid according to a known method [J. Org. Chem., 48:5406 (1983)], followed by heating at temperature from 100° to 250° C. inthe presence of a catalytic amount of hydroquinone in each case.

Compound (D") is prepared by reacting the aldehyde (C") with 0.5 to 5mol equivalent of Wittig reagent such as carbomethoxyethylidenetriphenylphosphorane or the like or an anion made from Wittig-Hornerreagent such as ethyl 2-(diethylphosphono)propionate, ethyl2-(dimethylphosphono)propionate or the like at temperature from -50° to100° C. in a solvent such as diethyl ether, THF, DMF, dichloromethane orthe like.

Compound (D"), when treated with 0.5 to 10 mol equivalent of metalhydride complex such as lithium aluminium hydride or the like attemperature from -70° to 100° C. in an ether solvent such as diethylether, THF or the like or with 0.5 to 10 mol equivalent of metal hydridesuch as dibutylaluminium hydride or the like at temperature from -70° to100° C. in a hydrocarbon solvent such as benzene, toluene, n-hexane,n-heptane or the like, gives Compound (E"), which is a compound offormula I wherein n is 1, X is hydroxyl ##STR56## , which is the same asCompound (E') in the synthetic route 2.

Compound (F) can be prepared from Compound (E") by halogenating theallylic alcoholic without allyl rearrangement as previously described inthe synthetic route 2. Compound (E"), when treated in the same manner asmentioned above, gives sarcophytol A.

As can be seen from the above, sarcophytol A can be prepared effectivelyfrom the compound (I) of the invention through various processes usingor without using the intermediate F, which demonstrates that thecompound (I) is highly useful and important for the attainment of thepurpose of this invention.

Following Examples are provided for purposes of illustration only andare not to be construed as limiting the scope of the instant inventionin any way. ##STR57##

A mixture of 8-acetoxy-2,6-dimethyl-2,6-octadiene-1-ol (1.81 g, 8.52mmol) and dihydropyran (1.17 ml, 12.8 mmol) in dichloromethane (6 ml)was stirred, and p-toluenesulfonic acid (40 mg) was added thereto, andthe mixture was stirred at room temperature for 30 minutes. Afteraddition of saturated aqueous sodium bicarbonate (30 ml), the productwas extracted with hexane/ether (5:1.1) (30 ml). The extract was driedover Na₂ SO₄ and evaporated in vacuo to remove the solvent to give aresidue, which was purified with silica gel column chromatography togive 1-acetoxy-8-(2-tetrahydropyranyl)oxy-3,7-dimethyl-2,6-octadiene(2.42 g, 96%). ##STR58##

A mixture of 8-acetoxy-2,6-dimethyl-2,6-octadien-1-ol (110 mg, 0.52mmol) and triethylamine (0.25 ml, 1.83 mmol) and chloromethyl methylether (0.069 ml, 0.92 mmol) in acetonitrile (2 ml) was refluxed withstirring for 4 hours. After addition of water (3 ml) to the reactionmixture, the product was extracted several times with ether (5 ml). Theextract was dried over Na₂ SO₄ and evaporated in vacuo to remove thesolvent to give a residue, which was then subjected to silica gel columnchromatography to give the aimed1-acetoxy-8-(2-methoxymethyl)oxy-3,7-dimethyl-2,6-octadiene (109 mg,82%). ##STR59##

8-Acetoxy-2,6-dimethyl-2,6-octadien-1-ol in dimethylformamide (4 ml) wasstirred on an ice bath. To the solution were added imidazole (338 mg,4.96 mmol) and chlorodimethyl t-butylsilane (410 mg, 2.73 mmol), and themixture was stirred at room temperature for one hour. After addition ofwater (30 ml) to the reaction mixture, the product was extracted withhexane (20 ml×2). The extract was dried over MgSO₄ and evaporated invacuo to remove the solvent to give a residue, which was subjected tosilica gel column chromatography to obtain 1-acetoxy-8-(dimethylt-butylsilyl)oxy-3,7-dimethyl-2,6-octadiene (606 mg, 75%).

EXAMPLE 1 ##STR60##

To a solution of1-acetoxy-8-(2-tetrahydropyranyl)oxy-3,7-dimethyl-2,6-octadiene (1.08 g,3.64 mmol) in tetrahydrofuran (6 ml) were added under nitrogenatmosphere triphenylphosphine (105 mg, 0.4 mmol) andtetrakis(triphenylphosphine)paradium (168 mg, 0.15 mmol), and themixture was stirred at room temperature for 15 minutes. To the mixturewere added a sodium salt of methyl acetoacetate in tetrahydrofuran (25ml) which has been prepared from sodium hydride (305 mg, 12.7 mmol) andmethyl acetoacetate (1.57 ml, 14.6 mmol), and the mixture was refluxedfor 5 hours. After addition of water (10 ml) and ether (30 ml), thereaction mixture was stirred well, and the organic layer was separated.The aqueous layer was extracted with ether (5 ml), and the extract wasdried over Na₂ SO₄ and evaporated in vacuo to remove the solvent to givea residue, which was then subjected to silica gel column chromatographyto obtain purified methyl2-acetyl-5,9-dimethyl-10-(2-tetrahydropyranyl)oxy-4,8-decadienate (1.06g, 83%).

IR(film)cm⁻¹ ; 2950, 2870, 1750, 1722, 1440, 1360, 1201, 1150, 1022.

NMR (CDCl₃, 250 MHz)δppm; 1.45-1.92 (m, 6H, C(O)H₂ --CH₂ --CH₂ --CHO--),1.63, 1.65 (2S, 6H, 2x--CH₃ C═CH--), 1.94-2.15 (m, 4H, --C═CH--CH₂ --CH₂--C═CH--), 2.22 (s, 3H, CH₃ C═O), 3.46 (t, J=7.5 Hz, 1H, --CHCO2-), 3.53(m, 1H, --CH₂ --CHaHb--O--), 3.73 (s, 3H, CO2CH₃), 3.83, 4.09 (2d,J=11.8 Hz, 2H, --OCH₂ C═CH--), 3.82-3.94 (m, 1H, --CH₂ --CHaHb--O--),4.60 (t, J=3.4 Hz, 1H, --OCHO--), 5.04 (t, J=7.3 Hz, 1H, --C═CH--CH₂--), 5.38 (t, J=6.2 Hz, 1H, --C═CH--CH₂ --).

EXAMPLE 2 ##STR61##

To a solution of1-acetoxy-8-(methoxymethyl)oxy-3,7-dimethyl-2,6-octadiene (600 mg, 2.34mmol) in tetrahydrofuran (6 ml) were added under nitrogen atmospheretriphenylphosphine (60 mg, 23 mmol) andtetrakis(triphenylphosphine)paradium (108 mg, 0.09 mmol), and themixture was stirred at room temperature for 15 minutes. To the mixturewere added a sodium salt of methyl acetoacetate in tetrahydrofuran (25ml) which has been prepared from sodium hydride (225 mg, 9.36 mmol) andmethyl acetoacetate (1.26 ml, 11.7 mmol), and the mixture was refluxedfor 2 hours. After addition of water (40 ml) and ether (50 ml), thereaction mixture was stirred well, and the organic layer was separated.The aqueous layer was extracted with ether (50 ml), and the extract wasdried over Na₂ SO₄ and evaporated in vacuo to remove the solvent to givea residue, which was then subjected to silica gel column chromatographyto obtain purified methyl2-acetyl-5,9-dimethyl-10-(methoxymethyl)oxy-4,8-decadienate (670 mg,92%).

IR(film)cm⁻¹ ; 2930, 1745, 1720, 1438, 1355, 1208, 1150, 1100, 1040,920.

¹ H NMR(CDCl₃, 250 MHz)δppm; 1.63, 1.65 (2s, 6H, CH₃ C═CH--x2),1.93-2.17 (m, 4H, --C═CH--CH₂ --CH₂ --C═CH--), 2.22 (s, 3H, COCH₃), 2.56(t, J=7.4 Hz, 2H, --C═CH--CH₂ --CH(CO2CH₃)--), 3.38 (s, 3H, CH₃ OCH₂O--), 3.46 (t, J=7.5 Hz, 1H, CH(CO2CH₃)), 3.73 (s, 3H, CO2CH₃), 3.92 (s,2H, --OCH₂ C═CH--), 4.61 (s, 2H, --OCH₂ O--), 5.04 (t, J=7.3 Hz, 1H,--C═CH--CH₂ --), 5.38 (t, J=6.7 Hz, 1H, --C═CH--CH₂ --).

EXAMPLE 3 ##STR62##

To a solution of 1-acetoxy-8-(dimethoxy t-butylsily)oxy-3,7-dimethyl-2,6octadiene (600 mg, 1.84 mmol) in tetrahydrofuran (5ml) were added under nitrogen atmosphere triphenylphosphine (47 mg, 0.18mmol) and tetrakis (triphenylphosphine)paradium (81 mg, 0.07 mmol), andthe mixture was stirred at room temperature for 15 minutes. To themixture was added a sodium salt of methyl acetoacetate intetrahydrofuran (20 ml) which has been prepared from sodium hydride (92mg, 8.0 mmol) and methyl acetoacetate (0.99 ml, 9.20 mmol), and themixture was refluxed overnight. After addition of water (10 ml) andether (30 ml), the reaction mixture was stirred well, and the organiclayer was separated. The aqueous layer was extracted with ether (5ml×2), and the extract was dried over Na₂ SO₄ and evaporated in vacuo toremove the solvent to give a residue, which was then subjected to silicagel column chromatography to obtain purified methyl2-acetyl-10-(dimethyl t-butylsilyl)oxy- 5,9-dimethyl-4,8-decadienate(620 mg, 88%).

IR(film)cm⁻¹ ; 2970, 2940, 2910, 2860, 1745, 1722, 1435, 1360, 1250,1065, 837, 775.

¹ H NMR(CDCl₃, 250 MHz)δppm; 0.06, (s, 6H, (CH₃)₂ Si), 0.90 (s, 9H,(CH₃)₃ CSi), 1.59, 1.63 (2s, 6H, 2xCH₃ C═CH--), 1.92-2.15 (m, 4H,--C═CH--CH₂ --CH₂ --C═CH--), 2.22 (s, 3H, --CHCH₃), 2.55 (t, J=7.4 Hz,2H, --C═CH--CH₂ --CH(CO2CH₃)), 3.46 (t, J=7.4 Hz, 1H, --CH(CO2CH₃)),3.73 (s, 3H, --CO2CH₃), 3.99 (s, 2H, SiOCH₂), 5.04 (t, J=6.7 Hz, 1H,--C═CH--CH₂ --), 5.33 (t, J=6.8 Hz, 1H, --C═CH--CH₂ --).

EXAMPLE 4 ##STR63##

To a solution of methyl2-acetyl-5,9-dimethyl-10-(2-tetrahydropyranyl)oxy-4,8-decadienate (370mg, 1.05 mmol) in methylsulfoxide (2 ml) were added sodium chloride (180mg, 3.08 mmol) and water (0.1 ml), and the mixture was stirred at 150°C. After four hours, the reaction mixture was allowed to cool to roomtemperature, and water (15 ml) was added thereto. The product wasextracted with ether (20 ml×2). The extract was dried over Na₂ SO₄, andconcentrated to give a residue, which was then purified with silica gelcolumn chromatography to obtain6,10-dimethyl-11-(2-tetrahydropyranyl)oxy-5,9-undecadien-2-one (70%).

IR(film)cm⁻¹ ; 2950, 2880, 1720, 1442, 1358, 1120, 1078, 1024, 905, 870,815.

¹ H NMR(CDCl₃, 250 MHz)δppm; 1.45-1.90 (m, 6H, --OCH₂ --CH₂ --CH₂ --CH₂--CH(O)), 1.62, 1.65 (2s, 6H, (CH₃)C═CH--CH₂ --CH₂ --(CH₃)C═CH--),1.96-2.20 (m, 4H, --C═CH--CH₂ --CH₂ --C═CH--), 2.14 (s, 3H, COCH₃), 2.26(q, J=7.1 Hz, 2H, --C═CH--CH₂ --CH₂ CO--), 2.46 (t, J=7.1 Hz, 2H, --CH₂COCH₃), 3.45-3.55 (m, 1H, OCHaHb--CH₂ --CH₂ --CH₂ --CH(O)), 3.84, 4.10(2d, J=11.5 Hz, --OCH₂ C═CH--), 3.80-3.95 (m, 1H, OCHaHb--CH₂ --CH₂--CH₂ --), 4.60 (t, J=3.6 Hz, 1H, CH(O)), 5.08 (t, J=7.1 Hz, --C═CH--CH₂--CH₂ --C═CH--), 6.9 (t, J=6.9 Hz, 1H, --C═CH--CH₂ --CH₂ --C═CH--).

EXAMPLE 5 ##STR64##

To a solution of methyl2-acetyl-5,9-dimethyl-10-(methoxymethyl)oxy-4,8-decadienate (420 mg,1.37 mmol) in methylsulfoxide (4 ml) were added sodium chloride (160 mg,2.74 mmol) and water (0.1 ml), and the mixture was stirred at 150° C.After five hours, the reaction mixture was allowed to cool to roomtemperature, and water (10 ml) was added thereto. The product wasextracted with ether (20 ml×2). The extract was dried over Na₂ SO₄, andconcentrated to give a residue, which was then purified with silica gelcolumn chromatography to obtain 6,10-dimethyl-11-(methoxymethyl)oxy-5,9-undecadien-2-one (358 mg, 67%),

IR(film)cm⁻¹ ; 2940, 1720, 1440, 1358, 1150, 1100, 1050, 920.

¹ H NMR (CDCl₃, 250 MHz)δppm; 1.62, 1.66 (2s, 6H, 2×CH₃ C═CH--),1.94-2.32 (m, 6H, --C═CH--CH₂ --CH₂ --C═CH--CH₂ --), 2.14 (s, 3H,COCH₃), 2.46 (t, J=7.3 Hz, 2H, --CH₂ COCH₃), 3.38 (s, 3H, CH₃ O), 3.92(s, 2H, OCH₂ C═CH--), 4.61 (s, 2H, --OCH₂ C--), 5.08 (t, J=6.1 Hz, 1H,--C═CH--CH₂ --), 5.40 (t, J=6.7 Hz, 1H, --C═CHCH₂ --).

EXAMPLE 6 ##STR65##

To a solution of methyl 2-acetyl-10-(dimethylt-butylsilyl)oxy-5,9-dimethyl-4,8-decadienate (96 mg, 0.25 mmol) inhexamethylphosphoric triamide (0.5 ml) were added sodium iodide (45 mg,0.30 mmol) and water (0.01 ml), and the mixture was stirred at 150° C.After two hours, the reaction mixture was allowed to cool to roomtemperature, and water (2 ml) was added thereto. The product wasextracted with ether (5 ml×2). The extract was dried over Na₂ SO₄, andconcentrated to give a residue, which was then purified with silica gelcolumn chromatography to obtain 6,10-dimethyl-11-(dimethylt-butylsilyl)oxy-5,9-undecadien-2-one (57 mg, 70%).

IR(film)cm⁻¹ ; 2970, 2950, 2910, 2870, 1725, 1465, 1360, 1255, 1155,1110, 1070, 837, 775, 662.

¹ H NMR(CDCl₃, 250 MHz)δppm; 0.06 (s, 6H, (CH₃)₂ Si), 0.91 (s, 9H,(CH₃)₃ CSi), 1.59, 1.62 (2s, 6H, 2x--C═CH--CH₂ --), 1.92-2.32 (m, 6H,--CH═CH--CH₂ --CH₂ --), 2.14 (s, 3H, COCH₃), 2.46 (t, J=8.7 Hz, 2H, CH₂COCH₃), 4.00 (s, 2H, SiOCH₂ --), 5.08, 5.35 (2m, 2H, --C═CH--CH₂ --x2).

EXAMPLE 7

The procedures described in Examples 4-6 were repeated except thatmethyl 2-acetyl-5,9-dimethyl-10-(benzoyl)oxy-4,8-decadienate wasemployed as a starting material to give6,10-dimethyl-11-(benzoyl)oxy-5,9-undecadien-2-one.

EXAMPLE 8 ##STR66##

A solution of 6,10-dimethyl-11-(2-tetrahydropyranyl)oxy-5,9-undecadien-2-one (90 mg, 0.31 mmol) in tetrahydrofuran (5 ml)was stirred on an ice bath under argon atmosphere. To the solution wasadded lithium acetylide ethylenediamine complex (180 mg, 1.95 mmol), andthe mixture was warmed to room temperature and stirred for 3 hours.After addition of saturated aqueous ammonium chloride (2 ml), thereaction mixture was extracted with ether. The extract was dried overNa₂ SO₄ and evaporated in vacuo to remove the solvent to give a crudeproduct, which was purified with silica gel column chromatography toobtain3,7,11-trimethyl-12-(2-tetrahydropyranyl)oxy-6,10-dodecadien-1-in-3-ol(75 mg, 75%).

IR(film)cm⁻¹ ; 3440, 3320, 2950, 2880, 2200, 1440, 1450, 1382, 1360,1260, 1200, 1180, 1115, 1075, 1020, 905, 865, 810.

¹ H NMR(CDCl₃, 250 MHz)δppm; 1.50 (s, 3H, CH₃ C(OH)), 1.45-1.90 (m, 8H,OCH₂ --CH₂ --CH₂ --CH₂ --CH(O), --CH₂ C(OH), 1.65 (s, 6H, 2xCH₃ C═CH--),2.00-2.40 (m, 7H, --C═CH--CH₂ --CH₂ --C═CH--CH₂ --, OH), 2.46 (s, 1H,--Cu₋₋ C--H), 3.45-3.57 (m, 1H, --OCHaHb--CH₂ --), 3.84, 4.10 (2d,J=11.5 Hz, 2H, OCH₂ C═CH--), 3.80-3.94 (m, 1H, --OCHaHb--CH₂ --), 4.60(t, J=3.4 Hz, 1H, --OCHO--), 5.19 (t, J=6.7 Hz, 1H, --C═CH--CH₂ --),5.41 (t, J=6.7 Hz, 1H, --C═CH--CH₂ --).

EXAMPLE 9 ##STR67##

A solution of 6,10-dimethyl-11-(methoxymethyl)oxy-5,9-undecadien-2-one(67 mg, 0.26 mmol) in tetrahydrofuran (2 ml) was stirred on an ice bathunder argon atmosphere. To the solution was added lithium acetylideethylenediamine complex (30 mg, 0.33 mmol), and the mixture was warmedto room temperature and stirred for 3 hours. After addition of saturatedaqueous ammonium chloride (2 ml), the reaction mixture was extractedwith ether. The extract was dried over Na₂ SO₄ and evaporated in vacuoto remove the solvent to give a crude product, which was purified withsilica gel column chromatography to obtain3,7,11-trimethyl-12-(methoxymethyl)oxy-6,10-dodecadien-1-in-3-ol (61 mg,83%).

IR(film)cm⁻¹ ; 3450, 3300, 2940, 1445, 1370, 1148, 1045, 918.

¹ H NMR(CDCl₃, 250 MHz)δppm; 1.05 (s, 3H, CH₃ C(O)), 1.55-1.84 (m, 9H,2xCH₃ C═CH--, OH), 2.00-2.40 (m, 6H, --C═CH--CH₂ --CH₂ --C═CH--CH₂ --),2.46 (s, 1H, --C═C--H), 3.78 (s, 3H, CH₃ O), 3.92 (s, 2H, --OCH₂C═CH--), 4.61 (s, 2H, OCH₂ O), 5.19 (t, J=6.2 Hz, 1H, --C═CH--CH₂ --),5.41 (t, J=6.2 Hz, --C═CH--CH₂ --).

EXAMPLE 10 ##STR68##

A solution of 6,10-dimethyl-11-(dimethylt-butylsilyl)oxy-5,9-undecadien-1-one (71 mg, 0.22 mmol) intetrahydrofuran (2 ml) was stirred on an ice bath under argonatmosphere. To the solution was added lithium acetylide ethylenediaminecomplex (90 mg, 0.98 mmol), and the mixture was warmed to roomtemperature and stirred for 4 hours. After addition of saturated aqueousammonium chloride (2 ml), the reaction mixture was extracted with ether.The extract was dried over Na₂ SO₄ and evaporated in vacuo to remove thesolvent to give a crude product, which was purified with silica gelcolumn chromatography to obtain 3,7,11-trimethyl-12-(dimethylt-butylsilyl)oxy-6,10-dodecandien-1-in-3-ol (51 mg, 67%).

IR(film)cm⁻¹ ; 3450, 3320, 2960, 2940, 2910, 2860, 1460, 1360, 1250,1110, 1065, 835, 775.

¹ H NMR(CDCl₃, 250 MHz)δppm; 0.06 (s, 6H, (CH₃)₂ Si), 0.91 (s, 9H,(CH₃)₃ Si), 1.50 (s, 3H, --CH₂ --C(OH)(CH₃)--C═H), 1.59, 1.66 (2s, 6H,2xCH₃ C═CH--), 1.68-1.76 (m, 2H, --CH₂ C(OH)--), 1.94-2.36 (m, 7H,--C═CH--CH₂ --CH₂ --C═CH--CH₂ --, OH), 2.46 (s, 1H, --C═CH), 4.00 (s,2H, OCH₂ --C═CH--), 5.19 (t, J=7.1 Hz, 1H, --C═CH--CH₂ --), 5.36 (t,J=6.9 Hz, 1H, --C═CH--CH₂ --).

EXAMPLE 11 AND 12

The procedure described in Example 9 was repeated except that6,10-dimethyl-11-acetoxy-5,9-undecadien-2-on or6,10-dimethyl-11-(benzoyl)oxy-5,9-undecadien-2-one as employed as astarting material to give3,7,11-trimethyl-12-acetoxy-6,10-dodecadien-1-in-3-ol and3,7,11-trimethyl-12-(benzoyl)oxy-6,10-dodecadien-1-in-3-ol.

EXAMPLE 13

The procedures described in Examples 8 and 10 were repeated except that2,6-dimethyl-2,6-dodecandein-10-on-1-ol was employed as a startingmaterial to give 2,6,10-trimethyl-2,6-dodecadien-11-in-1,10-diol.

EXAMPLE 14 ##STR69##

A solution of 6,10-dimethyl-11-(2-tetrahydropyranyl) tetrahydropyranyl)oxy-5,9-undecadien-2-one (80 mg, 0.27 mmol) in tetrahydrofuran (3 ml)was stirred on an ice bath under argon atmosphere. To the solution wasadded vinylmagnesium bromide in tetrahydrofuran (0.3 ml, 0.3 mmol,1.0M), and the mixture was warmed to room temperature and stirred for 10hours. After addition of saturated aqueous ammonium chloride (2 ml), thereaction mixture was extracted with ether. The extract was dried overNa₂ SO₄ and evaporated in vacuo to remove the solvent to give a crudeproduct, which was purified with silica gel column chromatography toobtain3,7,11-trimethyl-12-(2-tetrahydropyranyl)oxy-1,6,10-dodecatrien-3-ol (61mg, 70%).

IR(film)cm⁻¹ ; 3460, 2950, 2880, 1200, 1118, 1075, 1022, 905, 865, 810.

¹ H NMR(CDCl₃, 250 MHz)δppm; 1.28 (s, 3H, C(OH)CH₃), 1.65-1.92 (m, 8H,--OCH₂ --CH₂ --CH₂ --CH₂ --CH(O)--, CH₂ --C(OH)), 1.95-2.40 (m, 7H,C═CH--CH₂ --CH₂ --C═CH--CH₂ --, OH), 3.45-3.55 (m, 1H, --OCHaHb--CH₂--), 3.84, 4.10 (2d, J=11.6 Hz, 2H, --OCH₂ C═CH₂ --), 3.80-3.95 (m, 1H,--OCHaHb--CH₂ --), 4.60 (t, J=3.4 Hz, 1H, OCH(O)), 5.06 (dd, J=1.3, 10.7Hz, 1H, --CH═CHaHb), 5.14 (m, 1H, --C═CH--CH₂ --), 5.22 (dd, J=1.3, 17.4Hz, 1H, --CH═CHaHb), 5.41 (t, J= 6.3 Hz, 1H, --C═CH--CH₂ --), 5.92 (dd,J=10.7, 17.4 Hz, 1H, --CH═CH₂).

EXAMPLE 15 ##STR70##

A solution of 6,10-dimethyl-11-(methoxymethyl)oxy-5,9-undecadien-2-one(60 mg, 0.24 mmol) in tetrahydrofuran (2 ml) was stirred on an ice bathunder argon atmosphere. To the solution was added vinylmagnesium bromidein tetrahydrofuran (1.0 ml, 1.0 mmol, 1.0M), and the mixture was warmedto room temperature and stirred for 4 hours. After addition of saturatedaqueous ammonium chloride (2 ml), the reaction mixture was extractedwith ether. The extract was dried over Na₂ SO₄ and evaporated in vacuoto remove the solvent to give a crude product, which was purified withsilica gel column chromatography to obtain3,7,11-trimethyl-12-(methoxymethyl)oxy-1,6,10-dodecatrien-3-ol (54 mg,80%).

IR(film)cm⁻¹ ; 3480, 2940, 1450, 1370, 1210, 1150, 1100, 1045, 920, 845,685.

¹ H NMR(CDCl₃, 250 MHz)δppm; 1.28 (s, 3H, CH₃ C(OH)), 1.60, 1.66 (2s, 6H2xCH₃ --CH═C--), 1.52-1.72 (m, 2H, --CH₂ --C(OH)), 1.95-2.20 (m, 7H,--C═CH--CH₂ --CH₂ --C═CH--CH₂ --, OH), 3.38 (s, 3H, CH₃ O), 3.92 (s, 2H,--OCH₂ C═CH--), 4.61 (s, 2H, --OCH₂ O--), 5.06 (dd, J=1.3, 10.7 Hz, 1H,--CH═CHaHb), 5.14 (t, J=7.2 Hz, 1H, --C═CH--CH₂ --), 5.20 (dd, J=1.3,17.4 Hz, 1H, --CH═CHaHb), 5.41 (t, J=6.9 Hz, 1H, --C═CH--CH₂ --), 5.92(dd, J=10.7, 17.4 Hz, 1H, --CH═CH₂ --).

EXAMPLE 16 ##STR71##

A solution of 6,10-dimethyl-11-(dimethyl-t-butylsilyl)oxy-5,9-undecadien-2-one (48 mg, 0.15 mmol) in tetrahydrofuran (2 ml)was stirred on an ice bath under argon atmosphere. To the solution wasadded vinylmagnesium bromide in tetrahydrofuran (10 ml, 1.0 mmol, 1.0M),and the mixture was warmed to room temperature and stirred for 4 hours.After addition of saturated aqueous ammonium chloride (2 ml), thereaction mixture was extracted with ether. The extract was dried overNa₂ SO₄ and evaporated in vacuo to remove the solvent to give a crudeproduct, which was purified with silica gel column chromatography toobtain3,7,11-trimethyl-12-(dimethyl-t-butylsilyl)oxy-1,6,10-dodecatren-1-3-ol(32 mg, 60%).

IR(film)cm⁻¹ ; 3420, 2970, 2940, 2860, 1462, 1360, 1250, 1150, 1070,920, 835, 775, 662.

¹ H NMR(CDCl₃, 250 MHz)δppm; 0.06 (s, 6H, (CH₃)₂ Si), 0.91 (s, 9H,(CH₃)₃ CSi), 1.28 (s, 3H, --C(OH)(CH₃)--CH═CH₂), 1.60 (s, 6H, 2xCH₃C═CH--), 1.46-1.73 (m, 3H, --CH₂ C(OH)(CH₃))--, 4.00 (s, 2H, SiOCH₂ --),5.06 (dd, J=1.3, 10.7 Hz, 1H, --CH═CHaHb), 5.14 (m, 1H, --C═CH--CH₂ --),5.22 (dd, J=1.3, 17.4 Hz, 1H, --CH═CHaHb), 5.36 (m, 1H, --C═CH--CH₂ --),5.92 (dd, J=10.7, 17.4 Hz, 1H, --CH═CH₂ --).

EXAMPLE 17

The procedure described in Example 14 was repeated except that6,10-dimethyl-11-(benzoyl)oxy-5,9-undecadien-2-one was employed as astarting material to give3,7,11-trimethyl12-(benzoyl)oxy-1,6,10-dodecatrien-3-ol.

EXAMPLE 18

The procedures described in Examples 15 and 16 were repeated except that2,6-dimethyl-2,6-undecadien-10-on-1-ol was employed as a startingmaterial to give 2,6,10-trimethyl-2,6,11-dodecatrien-1,10-diol.

EXAMPLE 19 ##STR72##

To a solution of 2-(diethylphosphono)isovaleronitrile (6.54 g, 30 mmol)in toluene (55 ml) was added a 0.5M solution of potassiumbis(trimethylsilyl)amide in toluene (56 ml) with stirring on a coolingbath at -70° C. After 30 minutes, geranial (3.80 g, 25 mmol) was addedthereto with continuous stirring at the same temperature, and then thereaction mixture was warmed up to room temperature. After addition ofwater to the mixture, the organic layer was extracted. The organicextract was washed with saturated aqueous sodium bicarbonate andsaturated aqueous sodium chloride, dried over MgSO₄, and filtered. Thefiltrate was concentrated to give a residue, which was then subjected tosilica gel column chromatography (solvent: n-hexane/ethyl acetate=100:1)to give 2-(1-methylethyl)-5,9-dimethyl-2,4,8-decatrieneitrile (4.87 g,90%, 2Z:2E=22.4:1).

Spectral Data of 2Z Compound

IR(film)cm⁻¹ ; 2980, 2940, 2890, 2220, 1640, 1450, 1390, 1375, 1295,1225, 1105, 1030.

¹ H NMR(CDCl₃, 250 MHz)δppm; 1.17 (d, J=6.8 Hz, 6H, CH(CH₃)₂), 1.61,1.69 (each bs, each 3H, --C═CCH₃), 1.83 (d, J=1.2 Hz, 3H, --C═CCH₃),2.0-12.2 (m, 4H, --CH₂ CH₂ --), 2.53 (hep, J=6.8 Hz, 1H, CH(CH₃)₂), 5.08(m, 1H, --C═CHCH₂ --), 6.28, 6.82 (each d, J=11.5 Hz, each 1H,═CH--CH═).

EXAMPLE 20 ##STR73##

To a solution of 2-(1-methylethyl)-5,9-dimethyl-2,4,8-decatrieneitril(2Z compound, 217 mg, 1 mmol) in n-hexane (4 ml) was added a 1M solutionof diisobutylaluminium hydride in toluene (2 ml) with stirring underargon atmosphere at -70° C. After two-hour-stirring at the sametemperature, water (0.8 ml) was added to the mixture followed by removalof the cooling bath and vigorous stirring. The resultant whileprecipitates were filtered and washed with n-hexane. The filtrate wascombined with a 10% aqueous solution of oxalic acid and stirred for 3hours. The organic layer was extracted and separated, washed with water,dried over MgSO₄, and concentrated. The above manipulation was conductedunder argon atmosphere. The resultant residue was subjected to silicagel column chromatography (solvent: n-hexane/ethyl acetate=50:1) toobtain the aimed 2-(1-methylethyl)-5,9-dimethyl-2,4,8-decatrienal (198mg, 90%).

IR(film)cm⁻¹ ; 2980, 2940, 2880, 1670, 1630, 1455, 1375, 1295, 1235,1135, 1105, 1075.

NMR(CDCl₃, 250 MHz)δppm; 1.07 (d, J=6.8 Hz, 6H, --CH(CH₃)₂), 1.62, 1.69(each bs, each 3H, --C═CCH₃), 1.89 (d, J=1.0 Hz, 3H, --C═CCH₃), 2.0-12.3(m, 4H, --CH₂ CH₂ --), 2.91 (hep, J=6.8 Hz, 1H, --CH(CH₃)₂), 5.10 (m,1H, ═CHCH₂ --), 6.83, 7.14 (each d, J=12.0 Hz, each 1H, ═CH--CH=), 10.29(s, 1H, --CHO).

EXAMPLE 21 ##STR74##

To a solution of 2-(diethylphosphono)isovaleronitrile (8.72 g, 40 mmol)in toluene (75 ml) was gradually added a 0.5M solution of potassiumbis(trimethylsilyl)amide in toluene (75 ml) with stirring at -70° C.under argon atmosphere. The cooling bath was removed, and the reactionmixture was stirred at room temperature for 30 minutes. The reactionmixture was cooled to -70° C. again, and farnesol (5.88 g, 26.7 mmol)was added thereto with stirring, and the mixture was allowed to warm toroom temperature. After addition of water, the organic layer wasseparated, washed with saturated aqueous sodium bicarbonate and thensaturated aqueous sodium chloride, and dried over MgSO₄. The organiclayer was separated from MgSO₄ by filtration and concentrated to give aresidue, which was purified with silica gel column chromatography(solvent: n-hexane/ethyl acetate=100:1) to obtain the aimed2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-tetradecatetraeneitrile(7.23 g, 96%; 2Z:2E=25.6:1).

Spectral Data of 2Z Compound

IR(film)cm⁻¹ ; 2980, 2940, 2210, 1640, 1450, 1390, 1290, 1225, 1110,1030.

NMR(CDCl₃, 250 MHz)δppm; 1.14 (d, J=6.8 Hz, 6H, CH(CH₃)₂), 1.58 (bs,3Hx2, --C═CCH₃), 1.65 (bs, 3H, --C═CCH₃), 1.81 (d, J=1.2 Hz, 3H,--C═CCH₃), 1.9-2.2 (m, 8H, --CH₂ CH₂ --x2), 2.50 (hep, J=6.8 Hz, 1H,--CH(CH₃)₂), 5.06 (m, 1H, ═CHCH₂ --), 6.26, 6.80 (each d, J=11.5 Hz,each 1H, ═CH--CH═).

EXAMPLE 22 ##STR75##

To a solution of2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-tetradecatetraenenitrile(856 mg, 3.0 mmol) in n-hexane (30 ml) was added a 0.5M solution ofdiisobutylaluminium hydride in toluene (6 ml) with stirring at -70° C.under argon atmosphere. After one hour, water (3 ml) was added, thecooling bath was removed, and the reaction mixture was stirred well.Resultant white precipitates were filtered and washed. The filtrate wasconcentrated to give a residue, which was dissolved in n-hexane (10 ml).The n-hexane solution was combined with a 10% aqueous solution of oxalicacid (5 ml) and stirred for 3 hours. The organic layer was extracted andseparated, washed with water, dried over MgSO₄, and concentrated. Theresultant residue was subjected to silica gel column chromatography(solvent: n-hexane/ethyl acetate=10:1) to obtain2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-tetradecatetraenal (865 mg,84%).

IR(film)cm⁻¹ ; 2980, 2940, 2210, 1640, 1450, 1390, 1290, 1225, 1110,1030.

NRM(CDCl₃, 250 MHz)δppm; 1.07 (d, J=6.8 Hz, 6H, --CH(CH₃)₂), 1.59, 1.61,1.67 (each bs, 3Hx3, --C═CCH₃), 1.89 (d, J=1.0 Hz, 3H, --C═CCH₃),2.0-2.2 (m, 8H, --CH₂ CH₂ --x2), 2.91 (hep, J=6.8 Hz, 1H, --CH(CH₃)₂),5.10 (m, 1H, --C═CCH₃), 6.81, 7.16 (each d, J=12.0 Hz, each 1H,═CH--CH═), 10.29 (s, 1H, --CHO).

EXAMPLE 23 ##STR76##

To a suspension of selenium dioxide (58 mg) and 2-hydroxybenzoic acid(365 mg) in methylene chloride (10.5 ml) was gradually added an aqueoussolution of 80% t-butyl hydroperoxide (11.6 ml) with stirring on a waterbath. After 30 minutes,2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-tetradecatetraenenitrile(7.56 g, 26.8 mmol) was added to the mixture, which was then allowed tostand at room temperature for 30 hours. Most of the solvent was removedby evaporation in vacuo, and the residue was dissolved in ether. Theorganic layer was washed with saturated aqueous sodium bicarbonate,dried over MgSO₄, and concentrated. The resultant residue was subjectedto silica gel column chromatography to give the aimed14-hydroxy-2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-tetradecatetraenenitrile(2.53 g, 31%). The starting material was also recovered (3.10 g, 40%) inthe column chromatography. The yield of the aimed product based on theconsumed starting material as 52%.

IR(film)cm⁻¹ ; 3450, 2975, 2930, 2880, 2210, 1635, 1445, 1385, 1220,1020.

NMR(CDCl₃, 250 MHz)δppm; 1.17 (d, J=6.7 Hz, 6H, CH(CH₃)₂), 1.62, 1.67(each bs, each 3H, --C═CCH₃), 1.84 (d, J=1.2 Hz, 3H, --C═CCH₃), 2.0-2.2(m, 8H, --CH₂ CH₂ --x2), 2.53 (hep, J=6.7 Hz, 1H, --CH(CH₃)₂), 3.99 (bs,2H, --CH₂ OH), 5.11 (m, 1H, --CHCH₂ --), 5.39 (bt, J=5.5 Hz, 1H, --CHCH₂--), 6.28, 6.83 (each d, J=11.5 Hz, each 1H, ═CH--CH═).

EXAMPLE 24 ##STR77##

To a solution of14-hydroxy-2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-tetradecatetraenenitrile(904 mg, 3.0 mmol) in carbon tetrachloride (2 ml) was addedtriphenylphosphine (1.02 g, 3.9 mmol), and the mixture was heated underreflux for one hour. Most of carbon tetrachloride was removed byevaporation in vacuo, and n-hexane was added to the residue. Theresultant mixture was filtered and washed and the filtrate wasconcentrated to give a residue, which was then subjected to silica gelcolumn chromatography (solvent: n-hexane/ethyl acetate=10:1) to obtainthe aimed 14-chloro compound (890 mg, 93%).

IR(film)cm⁻¹ ; 2980, 2940, 2880, 2215, 1635, 1445, 1390, 1265, 1025.

NMR(CDCl₃, 250 MHz)δppm; 1.14 (d, J=6.8 Hz, 6H, CH(CH₃)₂), 1.59, 1.64(each bs, each 3H, --C═CCH₃), 1.81 (d, J=1.0 Hz, 3H, --C═CCH₃), 1.9-2.2(m, 8H, --CH₂ CH₂ --x2), 2.50 (hep, J=6.8 Hz, 1H, --CH(CH₃)₂), 3.96 (bs,2H, --CH₂ OH), 5.08 (m, 1H, --CHCH₂ --), 5.36 (bt, J=5.5 Hz, 1H, ═CHCH₂--), 6.25, 6.80 (each d, J=11.5 Hz, each 1H, ═CH--CH═).

The following Reference Examples illustrate a method of preparation ofsarcophytol A by the use of the compounds obtained in the foregoingExamples.

REFERENCE EXAMPLE 1 ##STR78##

A solution of3,7,11-trimethyl-12-(methoxymethyl)oxy-6,10-dodecadien-1-in-3-ol (175mg, 0.62 mmol), tris (triphenylsilyl)vanadate (49 mg, 0.062 mmol), andbenzoic acid (7.6 mg, 0.062 mmol) in xylene (2 ml) as stirred on an oilbath at 140° C. After two-hour-stirring, the solution was allowed tocool to room temperature and concentrated. The resultant residue wassubjected to silica gel column chromatography to obtain12-(methoxymethyl)oxy-3,7,11-trimethyl-2,6,10-dodecatrienal (88 mg,50%).

IR(film)cm⁻¹ ; 2950, 1675, 1450, 1385, 1198, 1157, 1120, 1105, 1050,925, 850.

¹ H NMR(CDCl₃, 250 MHz)δppm; 1.57, 1.62, 2.13 (each s, each 3H, CH₃C═CH--), 1.93-2.30 (m, 8H, 2x--C═CH--CH₂ --CH₂ `--), 3.33 (s, 3H, CH₃O), 3.88 (s, 2H, --OCH₂ C═CH--), 4.57 (s, 2H, --OCH₂ O--), 5.06, 5.36(each m, each 1H, --C═CH--CH₂ --), 5.84 (d, J=8.2 Hz, 1H, --C═CH--CHO),9.96 (d, J=8.2 Hz, 1H, --C═CH--CHO).

REFERENCE EXAMPLE 2 ##STR79##

A solution of3,7,11-trimethyl-12-(methoxymethyl)oxy-1,6,10-dodecatrien-3-ol (460 mg,1.6 mmol) in dichloromethane (30 ml) was added pyridinium chlorochromate(690 mg, 3.2 mmol), and the mixture was stirred at room temperature for8 hours. After addition of a mixture of hexane, ethyl acetate, and ether(3:1:1) (100 ml), the mixture was stirred and insoluble materials werefiltered. The filtrate was concentrated in vacuo, and the residue aspurified with silica gel column chromatography to give12-(methoxymethyl)oxy-3,7,11-trimethyl-2,6,10-dodecatrienal (233 mg,52%). The physico-chemical properties of the product was the same asthose described in Reference Example 1.

REFERENCE EXAMPLE 3 ##STR80##

to a solution of 2-(diethylphosphono)isovaleronitrile (316 mg, 1.44mmol) in toluene (1 ml) was dropwise added a 1.0M solution of lithiumbis(trimethylsilyl)amide in hexane (1.3 ml, 1.3 mmol) with stirring at-70° C. After 30 minutes,12-(methoxymethyl)oxy-3,7,11-trimethyl-2,6,10-dodecatrienal (130 mg,0.46 mmol) in toluene (2 ml) was added at the same temperature, and themixture was allowed to warm to room temperature over about 3 hours. Anaqueous ammonium chloride (6 ml) was added and the mixture was extractedwith hexane. The extract as dried over Na₂ SO₄ and evaporated in vacuoto remove the solvent to give a residue, which was then subjected tosilica gel column chromatography (solvent: n-hexane/ethyl acetate=20:1)to obtain the aimed 2-(1-methylethyl)-14-(methoxymethyl)oxy-5,9,13-trimethyl-2,4,8,12-tetraeneitrile (135 mg,85%).

IR(film)cm⁻¹ ; 2980, 2945, 2900, 2310, 1640, 1150, 1050.

1N NMR(CDCl₃, 250 MHz)δppm; 1.17 (d, J=6.8 Hz, 6H, (CH₃)₂ CH--), 1.61,1.67, 1.84 (each s, each 3H, CH₃ C═CH--), 1.96-2.21 (m, 8H, --C═CH--CH₂--CH₂ --C═CH--CH₂ --CH₂ --), 2.53 (hep, J=6.8 Hz, 1H, --CH(CH₃)₂), 3.38(s, 3H, CH₃ O--), 3.92 (s, 2H, --OCH₂ O--), 4.62 (s, 2H, --O--CH₂--C═CH--), 5.10 (brs, 1H, --C═CH--), 5.42 (brt, J=6.4 Hz, 1H, --C═CH--),6.28, 6.82 (each d, J=11.5 Hz, each 1H, --C═CH--CH═C(CN)--).

REFERENCE EXAMPLE 4 ##STR81##

To the product obtained in Reference Example 3 (135 mg, 0.39 mmol) inmethanol (5 ml) was added a trace amount of conc. HCl, and the mixturewas heated with stirring at 60° C. for 6 hours. After addition ofsaturated aqueous sodium bicarbonate (20 ml), the reaction mixture wasextracted with ether (20 ml×2). The extract as dried over MgSO₄ andevaporated in vacuo to remove the solvent. The resultant residue waspurified with silica gel column chromatography (solvent:n-hexane/ether=5:1) to obtain the 14-hydroxy compound (96 mg, 82%).

IR(film)cm⁻¹ ; 3460, 2980, 2930, 2210, 1635, 1450, 1020.

¹ N NMR(CDCl₃, 250 MHz)δppm; 1.14 (d, J=6.8 Hz, 6H, (CH₃)₂ CH--), 1.58(m, 4H, CH₃ C═CH--, --OH), 1.65 (s, 3H, CH₃ C═CH--), 1.81 (d, J=1.1 Hz,3H, CH₃ C═CH--, 1.92-2.25 (m, 8H, --C═CH--CH₂ --CH₂ --(CH₃)C═CH--CH₂--CH₂ --), 2.51 (hep, J=6.8 Hz, 1H, (CH₃)₂ CH--), 3.97 (d, J=5.9 Hz, 2H,CH₂ OH), 5.08 (brs, 1H, --C═CH--), 5.36 (m, 1H, --C═CH--), 6.26, 6.80(each d, J=11.5 Hz, each 1H, --C═CH--CH═C(CN)).

REFERENCE EXAMPLE 5 ##STR82##

To the hydroxy compound obtained in Reference Example 4 in toluene (5ml) was dropwise added a 1M solution of diisobutylaluminium hydride intoluene (2.0 ml, 2.0 mmol) at -70° C. under argon atmosphere. Aftertwo-hour-stirring at -70° C., a 1M aqueous solution of oxalic acid (4.0ml) was added, and the mixture was allowed to warm gradually to roomtemperature with stirring under argon atmosphere. The organic layer waswashed with water and saturated aqueous sodium bicarbonate, dried overNa₂ SO₄, and evaporated in vacuo to remove the solvent. The resultantresidue was purified with silica gel column chromatography (solvent:n-hexane/ethyl acetate=7:1) to obtain the aimed formyl compound.

IR(film)cm⁻¹ ; 3430, 2960, 2920, 2870, 1670, 1630, 1450, 1390, 1295,1230, 1130, 1070, 1010.

¹ N NMR(CDCl₃, 250 MHz)δppm; 1.04 (d, 6H, J=6.8 Hz, --CH(CH₃)₂), 1.59(d, J=0.6 Hz, 3H, CH₃ --C═), 1.63 (brs, 3H, CH₃ --C═), 1.86 (d, J=1.2Hz, 3H, CH₃ --C═), 1.7-2.2 (m, 8H, --CH₂ CH₂ --), 2.88 (hep. J=6.8 Hz,1H, --CH(CH₃)₂), 3.95 (brs, 2H, --CH₂ OH), 5.09 (m, 1H, --CH₂ CH═), 5.38(brt, J=6.8 Hz, 1H, --CH₂ CH═), 6.80 (d, J=12.0 Hz, 1H, ═CH--CH═), 7.11(d, J=12.0 Hz, 1H, ═CH--CH═), 10.25 (s, 1H, --CHO).

REFERENCE EXAMPLE 6 ##STR83##

A solution of dry lithium chloride (64 mg, 1.5 mmol), 2,6-lutidine (0.23ml, 2.0 mmol) and hydroxy formyl compound (305 mg, 1.0 mmol) indimethylformamide (1.0 ml) was chilled on an ice water bath and mixedwith methane-sulfonyl chloride (160 mg, 1.4 mmol) with stirring in argonatmosphere. About 8 hours later, the starting material was confirmed todisappear, and the reaction mixture was dissolved in water and ether.The organic layer was washed with water, dried over magnesium sulfateand concentrated. The residue was chromatographed on a column of silicagel eluting with n-hexane: ethyl acetate (15:1) as an eluent to give theobjective chloroformyl compound (281 mg, 87%).

IR(film)cm⁻¹ ; 2970, 2930, 2880, 1670, 1630, 1445, 1390, 1295, 1265,1135.

NMR(CDCl₃, 250 MHz)δppm; 1.04 (d, J=7.0 Hz, 6H, --CH(CH₃)₂), 1.59, 1.70(each bs, each 3H, --C═CCH₃), 1.87 (d, J=1.3 Hz, 3H, --C═CCH₃), 1.9-2.2(m, 8H, --CH₂ CH₂ --), 2.89 (hep, J=7.0 Hz, 1H, --CH(CH₃)₂), 3.98 (bs,2H₂, --CH₂ Cl), 5.09 (m, 1H, --C═CHC H₂ --), 5.47 (bt, J=6.5 Hz, 1H,--C═CHCH₂ --), 6.82 (d, J=12.0 Hz, 1H, --C═CH --CH═C(CHO)--), 7.11 (d,J=12.0 Hz, --C═CH--CH═C(CHO)--), 10.27 (s, 1H, --CHO).

REFERENCE EXAMPLE 7 ##STR84##

To a solution of the nitrile(14-chloro-2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-tetradecatetraene-nitril)(890mg, 2.78 mmol) in n-hexane (30 ml) was dropwise added gradually a 1Msolution (4.2 ml) of diisobutylaluminum hydride in toluene at -70° C.under argon atmosphere. One hour later, 2 ml of water was added to themixture, and the bath was removed. The reaction mixture was vigorouslystirred, and the resultant solid was filtered and washed with n-hexane.The resultant filtrate was stirred still with 10% oxalic acid. Theorganic layer was washed, dried, filtered and concentrated. The residuewas chromatographed on a column of silica gel eluting with n-hexane:ethyl acetate (20:1) to give the objective formyl compound (781 mg,87%).

IR(film)cm⁻¹ ; 2970, 2930, 2880, 1670, 1630, 1445, 1390, 1295, 1265,1135.

NMR(CDCl₃, 250 MHz)δppm; 1.04 (d, J=7.0 Hz, 6H, --CH(CH₃)₂), 1.59, 1.70(each bs, each 3H, --C═CCH₃), 1.87 (d, J=1.3 Hz, 3H, --C═CCH₃), 1.9-2.2(m, 8H, --CH₂ CH₂ --), 2.89 (hep, J=7.0 Hz, 1H, --CH(CH₃)₂), 3.98 (bs,2H, --CH₂ Cl), 5.09 (m, 1H, --C═CHCH₂ --), 5.47 (bt, J=6.5 Hz, 1H,--CH═CHCH₂ --), 6.82 (d, J=12.0 Hz, 1H, --C═CH--CH═C(CHO)--), 7.11 (d,J=12.0 Hz, --C═CH--CH═C (CHO)--), 10.27 (s, 1H, --CHO).

REFERENCE EXAMPLE 8 ##STR85##

The above formyl compound,14-chloro-2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-tetradecatetraenal(640 mg, 2.0 mmol) was dissolved in trimethylsilylnitril (0.35 ml, 2.6mmol). To the solution on an ice-water bath was added with stirringunder argon atmosphere a trace amount of potassium cyanide/18-crown6-ether complex. Two hours later, disappearance of the starting compoundwas confirmed. Excessive trimethylsilylnitrile was evaporated off toobtain crude15-chloro-3-(1-methylethyl)-6,10,14-trimethyl-2-(trimethylsiloxy)-3,5,9,13-pentadecatetraenenitrile(647 mg, quantitative).

IR(film)cm⁻¹ ; 2960, 2930, 2880, 2320, 1445, 1255, 1080, 875, 845.

NMR(CDCl₃, 250 MHz)δppm; 1.11, 1.15 (each d, J=6.9 Hz, each 3H,--CH(CH₃)₂), 1.60, 1.71, 1.77 (each s, each 3H, --C═CCH₃), 1.9-2.2 (m,8H, --CH₂ CH₂ --), 2.64 (hep, J=6.9 Hz, 1H, --CH(CH₃)₂, 3.99 (s, 1H,--CH₂ Cl), 5.11 (m, 1H, --C═CHCH₂ --), 5.33 (s, 1H, --CHCN), 5.48 (bt,J=6.5 Hz, 1H, --C═CHCH₂ --), 6.04, 6.25 (each d, J=11.3 Hz, each 1H,--C═CH--CH═C--).

REFERENCE EXAMPLE 9 ##STR86##

A solution of the crude cyanohydrine trimethylsilyl ether (647 mg, 2.00mmol if it is 100% pure), which was obtained in Reference Example 8 intetrahydrofuran (25 ml) was dropwise added with stirring at 50°-55° C.under argon atmosphere over 30 minutes to a solution of 1M lithiumbis(trimethylsilyl)amide in tetrahydrofuran, which had been diluted with25 ml of tetrahydrofuran. After completion of the dropwise addition, thetetrahydrofuran was evaporated off in vacuo, and the residue wasdissolved in ethyl ether (30 ml), and the solution was washed withcooled 1N, HCl, water, and then saturated aqueous sodium chloride. Theorganic layer was dried over MgSO₄ and then concentrated to give aresidue, which was then subjected to silica gel column chromatography(solvent: n-hexane/ethyl acetate=50:1-5:1) to obtain the aimed cyclized2-(1-methylethyl)-5,9,13-trimethyl-1-trimethylsiloxy-2,4,8,12-cyclotetradecatetraen-1-carbonitrile(496 mg, 64%) and desilylated analogue (56 mg, 9%).

NMR Spectrum of 1-Trimethylsiloxy Compound

NMR(CDCl₃, 250 MHz)δppm; 0.23 (s, 9H, --Si(CH₃)₃), 1.09, 1.15 (each d,J=6.7 Hz, each 3H, --CH(CH₃)₂), 1.50, 1.62 (each bs, each 3H, --C═CCH₃),1.70 (d, J=1.3 Hz, 3H, --C═CCH₃), 2.0-2.2 (m, 8H, --CH₂ CH₂ --), 2.51(hep, J=6.7 Hz, 1H, --CH(CH₃)₂), 2.55, 2.65 (each d, J=14.2 Hz, each 1H,--CHa Hb CN--), 4.94 (bt, J=6.1 Hz, 1H, --C═CHCH₂ --), 5.15 (bt, J=5.6Hz, 1H, --C═CHCH₂ --), 6.17, 6.44 (each d, J=11.8 Hz, each 1H,--C═CH--CH═C--).

NMR Spectrum of 1-Hydroxy Compound

NMR(CDCl₃, 250 MHz)δppm; 1.15, 1.19 (each d, J=6.7 Hz, each 3H,CH(CH₃)₂), 1.55, 1.63, 1.69 (each s, each 3H, CH₃ --C═C--), 1.94-2.35(m, 8H, CH₂ --C═C--), 2.51 (hep, J=6.7 Hz, 1H, CH(CH₃)₂), 2.66, 2.73(each d, J=14.1 Hz, 2H, CHa Hb CCN), 2.89 (brs, 1H, OH), 4.93, 5.24(each brt, J=5.3 Hz, each 1H, --C═CH--CH₂ --), 6.22, 6.42 (each d,J=11.1 Hz, each 1H, --C═CH--CH═C--).

REFERENCE EXAMPLE 10 ##STR87##

The above cyanohydrine trimethylsily ether compound,2-(1-methylethyl)-5,9,13-trimethyl-1-trimethylsiloxy-2,4,8,12-cyclotetradecatetraen-1-carbonitrile(657 mg, 1.7 mmol) was dissolved in 10% aqueous tetrahydrofuran (10 ml).To the solution on an ice-water bath was added a solution of 1M tetran-butylammonium fluoride in tetrahydrofuran (0.02 ml), and the mixturewas stirred and then allowed to stand at room temperature for 2 days.Most of the tetrahydrofuran was removed in vacuo and the residue wasdissolved in ethyl ether. The ether layer was dried over MgSO₄,filtered, concentrated, and subjected to silica gel columnchromatography (solvent: n-hexane/ethyl acetate=30:1) to obtain theketone compound,2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-cyclotetradecatetraen-1-one(411 mg, 85%).

REFERENCE EXAMPLE 11 ##STR88##

To the above ketone compound,2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-cyclotetradecatetraen-1-one(137 mg, 0.48 mmol) in dry toluene (2.5 ml) was dropwise added withstirring on a cooling bath at -70° C. a solution of 1M diisobutylaluminium hydride in toluene (0.6 ml). One hour later, disappearance ofthe starting material was confirmed. After addition of water (0.25 ml)and removal of the cooling bath, the reaction mixture was stirred,followed by drying over MgSO₄, filtration, and concentration to give aresidue, which was subjected to silica gel column chromatography(solvent: n-hexane/ethyl acetate=12:1) to obtain the aimed sarcophytol A(125 mg, 88%).

REFERENCE EXAMPLE 12

Lithium aluminium hydride (80.0 mg, 2.11 mmol) was added to diethylether (5 ml) under argon atmosphere, and the mixture was stirred. To thesuspension was dropwise added at room temperature over 5 minutes asolution of (1R,2S)-(-)-N-methylephedrine (308 mg, 2.12 mmol) in diethylether (5 ml). After one hour reflux of the reaction mixture withstirring, N-ethylaniline (0.53 ml, 4.23 mmol) was dropwise added theretoover 5 minutes, and the mixture as refluxed with stirring additional onehour. The mixture was then cooled to -72° C., and a solution of theketone compound (136 mg, 0.475 mmol) obtained in Reference Example 10 indiethyl ether (3 ml) was gradually added thereto, and the mixture wasstirred for 6 hours at -72° C. After addition of 1N HCl (9 ml), theorganic layer was separated, washed with 3N HCl (5 ml×2), and dried overNa.sub. 2 SO₄. Removal of the solvent in vacuo gave a residue, which wasthen subjected to silica gel column chromatography to give opticallyactive sarcophytol A (81 mg, 60%) and nonreacted ketone compound (52 mg,37%).

Optical purity of the optically active sarcophytol A was determined tobe 87% by means of high pressure liquid chromatography using aseparating column for optical isomers, specifically CHIRALCELL OD(commercially available from Daisel Kagaku Kogyo), said analysis beingreferred to as "HPLC analysis using CHIRALCELL OD" hereinafter.

REFERENCE EXAMPLE 13

A solution of lithium aluminum hydride in diethyl ether (2.26 ml, 1.40mmol, 0.62M) was stirred under argon atmosphere. To the solution wasdropwise added (S)-2-(anilinomethyl)pyrolidine (296 mg, 1.68 mmol) indiethyl ether (3 ml) at room temperature over 10 minutes. The reactionmixture was stirred at room temperature additional one hour and thencooled to -72° C. To the mixture was gradually added the ketone compound(162 mg, 0.56 mmol) in diethyl ether (5 ml), which had been prepared inReference Example 10. After one hour stirring at -72° C., saturatedaqueous sodium bicarbonate (1 ml) was added, and the mixture was stirredat room temperature for 10 minutes. After addition of 1N HCl (15 ml) anddiethyl ether (20 ml), the organic layer was separated. The aqueouslayer was extracted with diethyl ether (20 ml), and the extract waswashed with saturated aqueous sodium chloride (20 ml), dried over Na₂SO₄, and evaporated in vacuo to remove the solvent. The resultantresidue was subjected to silica gel column chromatography to obtainoptically active sarcophytol A (126 mg, 78%).

Optical purity of the thus obtained sarcophytol A was 92% when measuredby LPLC analysis using CHIRALCELL OD. [═]²⁴ _(D) : +209.9° (C=0.372,CHCl₃)

REFERENCE EXAMPLE 14

A solution of lithium aluminium hydride in diethyl ether (2.94 ml, 2.0mmol, 0.68M) was stirred under argon atmosphere, and to the solution wasgradually added (S)-2-(2,6-xylidinomethyl)pyrrolidine (490 mg, 2.4 mmol)at room temperature, and the mixture was stirred at room temperature for2 hours. The reaction mixture was cooled to -74° C., and to the mixturewas dropwise added over 10 minutes a solution of the ketone compound (69mg, 0.24 mmol) in diethyl ether (3 ml), which had been prepared inReference Example 10. After one hour stirring at -74° C., saturatedaqueous sodium sulfonate (1 ml) was added, and the resultant mixture asstirred at room temperature for a while. After addition of diethyl ether(10 ml) and diluted HCl (20 ml), the organic layer was separated, andthe aqueous layer was extracted with diethyl ether (20 ml). The extractwas washed with saturated aqueous sodium chloride (20 ml), dried overNa₂ SO₄, and evaporated in vacuo to remove the solvent to give aresidue, which was subjected to silica gel column chromatography toobtain optically active sarcophytol A (61 mg, 88%).

Optical purity of the optically active sarcophytol A was 93% accordingto HPLC analysis using CHIRALCELL OD. [═]²⁴ _(D) : +204.4 (c=0.27,CHCl₃)

REFERENCE EXAMPLE 15

A suspension of tin (II) chloride (b 382 mg, 1.01 mmol) and(R)-1-methyl-2-(piperidinomethyl)pyrrodine (366 mg, 2.01 mmol) indichloromethane (6 ml) was cooled to -72° C. under argon atmosphere. Tothe suspension was added diisobutylaluminum hydride in toluene (1.0mmol), and the mixture was stirred for ten minutes. To the mixture wasgradually added at -72° C. a solution of the ketone compound (100 mg,0.349 mmol) in dichloromethane (3 ml). The reaction mixture was stirredfor 4 hours, and the stirring was continued at room temperature for 30minutes after addition of saturated aqueous sodium chloride (3 ml).Resultant precipitates were filtered by the use of sellite, and thefiltrate was dried over Na₂ SO₄ and evaporated in vacuo to remove thesolvent. The resultant residue was purified with silica gel columnchromatography to give optically active sarcophytol A (79.2 mg, 79%).

Optical purity of the sarcophytol A thus obtained was 42% according toHPLC analysis using CHIRALCELL OD. [═]²⁵ _(D) : +101.9° (c=0.54, CHCl₃)

INDUSTRIAL UTILITY

As stated above, the compounds (I) of the present invention are veryuseful as intermediates for preparing sarcophytol A which possesses ananti-carcinogenic promotor activity and anti-tumor activity. Thus, thepresent invention provides a method suitable for industrial productionof sarcophytol A.

What is claimed is:
 1. An acyclic terpene compound of the formula (I):##STR89## wherein R is a group of the formula: ##STR90## wherein R⁴ is--C═CH; X is a group of the formula: --OR⁵ wherein R⁵ is a hydrogenatom; and n is 0.